Pronova Biopharma Norge v. Teva Pharmaceuticals USA, Inc. (867 F. Supp. 2d 502, 2012)

United States District Court for the District of Delaware 2012-05-29

Citations

Full opinion text

OPINION

SUE L. ROBINSON, District Judge.

I. INTRODUCTION

This action arises out of the filing of Abbreviated New Drug Applications (“ANDAs”) by Teva Pharmaceuticals, USA, Inc. (“Teva”) and Par Pharmaceutical, Inc. and Par Pharmaceutical Companies, Inc. (collectively, “Par”) seeking to market versions of Lovaza® (omega-3-acid ethyl esters), used to treat hypertriglyceridemia. Plaintiff Pronova Biopharma Norge AS (“Pronova”) is the holder of approved New Drug Application (“NDA”) No. 021654 for Lovaza®. Pronova is the owner by assignment of U.S. Patent Nos. 5,656,667 (“the '667 patent”) and 5,502,077 (“the '077 patent”), which are listed in the Food and Drug Administration’s (“FDA’s”) publication titled “Approved Drug Products with Therapeutic Equivalence Evaluations” (known as the “Orange Book”) for Lovaza®. (Civ. No. 09-286, D.I. 74 at ¶¶ 8, 11, 21, 24)

In March 2009, Pronova received notification from Teva that Teva had filed ANDA No. 91-208 with a Paragraph IV certification alleging that the '667 and '077 patents are invalid, unenforceable, and/or not infringed by Teva’s generic erlotinib hydrochloride tablets. (Id. at ¶ 15) Pronova also received notification from Par that Par had filed ANDA No. 91-108 with a Paragraph IV certification as to the '667 and '077 patents. (Civ. No. 09-505, D.I. 78 at ¶ 17) On April 23, 2009, Pronova filed Civ. Nos. 09-286 and 09-305, alleging infringement of the '667 and '077 patents by Teva and Par, respectively. Teva and Par (collectively, “defendants”) asserted defenses of noninfringement and invalidity. (Civ. No. 09-286, D.I. 96; Civ. No. 09-305, D.I. 99) The cases were consolidated.

The parties filed their respective claim construction briefing, and a seven-day bench trial commenced March 29, 2011. The infringement and validity issues have been fully briefed post-trial. (D.I. 232, 233, 234) The 30-month statutory stay expired on or about May 10, 2012. (D.I. 208 at 2) On May 7, 2012, the court entered an order enjoining defendants from launching their generic products until the court’s decision issued. (D.I. 243, amended at D.I. 244)

The court has jurisdiction pursuant to 28 U.S.C. §§ 1331,1338(a) and 1400(b). Having considered the documentary evidence and testimony, the court makes the following findings of fact and conclusions of law pursuant to Fed.R.Civ.P. 52(a).

II. FINDINGS OF FACT AND CONCLUSIONS OF LAW

A. Technological Background

1. This case involves fatty acid compositions and pharmaceutical compositions containing fatty acids for the treatment or prophylaxis of hypertriglyceridemia, or high blood levels of triglycerides, a type of fat in the bloodstream that can contribute to the hardening or narrowing of arteries. Eicosapentaenoic acid (“EPA”), docosahenaeonic acid (“DHA”), henicosapentaenoic acid (“HPA”), docosapentaenoic acid (“DPA”) and arachidonic acid (“AA”) are examples of omega-3 and omega-6 fatty acids at issue in this case.

2. EPA and DHA are “lipids,” or fats, that can exist as free fatty acids, ethyl esters, or triglycerides. (D.I. 204 at 723:25-725:11) Fatty acids containing carbon-carbon double bonds are called “unsaturated” fatty acids. (D.I. 200 at 53:15-22) EPA and DHA may also be described as “omega-3 fatty acids” or “oo-3,” which designates them as polyunsaturated fatty acids (“PUFAs”) having a terminal double bond 3 carbons away from the methyl (- CH3) end of the fatty acid chain. (D.I. 200 at 53:23-54:8)

3. Alternatively, compounds may be referred to by the number of carbon atoms and double bonds. EPA, which contains 20 carbons and 5 double bonds, can be represented as C20:5. Likewise, DHA, which contains 22 carbons and 6 double bonds, can be denoted as C22:6. (D.I. 200 at 57:17-58:18)

4. High blood plasma levels of triglycerides are strongly associated with a risk of heart attack. (D.I. 203 at 545:25-546:10) For that reason, clinical practice guidelines recommend lowering triglyceride levels when they are elevated. (Id. at 545:25-546:10) Very high triglyceride levels can cause pancreatitis, an inflammatory condition of the pancreas that can be fatal if uncorrected. (Id. at 546:14-23) Hyperlipidemia is the medical term for several disorders of lipid metabolism that cause high levels of triglycerides or cholesterol. The standard classifications of hyperlipidemia denote the various patterns of blood lipid elevation, with Types lib, IV and V involving high triglycerides. (Id. at 547:2-23)

B. Patented Technology

1. '667 patent

5. The '667 patent, entitled “Fatty acid composition,” was filed June 6, 1995 and issued August 12, 1997. Priority is claimed to United Kingdom application no. GB 8819110, filed August 11,1988.

6. The specification explains that numerous prior art publications have reported that “dietary fish oil preparations containing omega-3 polyunsaturated fatty acids have an effect on serum cholesterol and blood platelet aggregation” by affecting the prostanoid system. ('667 patent, col. 1:37-45) The available data, however, conflicts on several points. (Id.) While EPA has been considered to be “the most important of the marine omega-3 polyunsaturated fatty acids partly because of its potent antiaggregatory action,” recent reports showed that “EPA alone does not have a significant effect on hypertension” and EPA with DHA did not affect blood pressure. (Id., col. l:58-col. 2:16) EPA does combat hypertension in pregnancy, however, which is thought to have a different biological cause. (Id. at col. 2:17-25) Further, while early studies indicated that fish oils lower total cholesterol and LDL-cholesterol (the “bad” cholesterol) and raise HDL-cholesterol (the “good” cholesterol), later studies revealed the opposite. (Id. at col. 2:28-39)

7. The inventors disclosed that they had now found that

fatty acid compositions containing a high concentration, of at least 80% by weight, of omega-3 fatty acids, salts or derivatives thereof, where EPA and DHA are present in relative amounts of 1:2 to 2:1, and constitute at least 75% of the total fatty acids, ha[ve] a surprisingly advantageous effect on all the above mentioned risk factors for cardiovascular diseases, but especially a good effect on mild hypertension, hypertriglyceridemia and on the coagulation factor VII phospholipid complex activity. It lowers serum LDL-cholesterol, increases serum HDL-cholesterol, lowers serum triglycerides, lowers systolic and diastolic blood pressure and the pulse rate and lowers the activity of the blood coagulation factor VH-phospholipid complex. Although the detailed biological mechanisms for the effects of the compositions according to present application are not explicitly known, there are indications of a surprising synergism between the action of EPA and of DHA.

(Id. at col. 2:50-67) The compositions of the invention are also described as being well-tolerated, without severe side effects. (Id. at col. 3:1-3) An “especially preferred composition” according to the invention “comprises at least 90% by weight of long chain, polyunsaturated omega-3 fatty acids of which EPA and DHA constitute at least 85% by weight of the total fatty acids and are present in a ratio of EPA:DHA from 1:1 to 2:1 especially about 3:2.” (Id. at col. 3:4-9)

8. The '667 patent also discloses a method for preparing the compositions of the invention, which results in a very low concentration of by-products and the significant reduction of contaminants. (Id. at col. 3:22-4:39)

9. It was determined that the test composition (described in table 1, below)

lowered total serum cholesterol “significantly” in patients with a total cholesterol over 7.0 mmol/liter and raised HDL cholesterol “significantly in the whole population.” (Id., col. 8:58-63) LDL cholesterol was also lowered (5-10%) in these patients but no significant effect was noted for patients with a total cholesterol less than 7.0 mmol/liter. (Id. at col. 8:64-67)

10. Pronova asserts that Teva’s ANDA infringes claims 20, 44 and 50 of the '667 patent; only claims 20 and 44 are asserted against Par. Claim 20 is a dependent claim, referring back to independent claim 14. Claims 14-20 are reproduced below.

14. A pharmaceutical mixed-fatty-acids composition in which

a) at least 80% by weight of the composition is comprised of a combination of (all-Z omega-3)-5,8,ll,14,17-eicosapentaenoic acid (EPA) and (all-Z omega-3)-4,7,10,13,16,19-docosahexaenoic acid (DHA) in a weight ratio of EPADHA of from 1:2 to 2:1 and

b) (all-Zomega-3)-6,9,12,15,18-heneicosapentaenoicacid is present in an amount of at least one percent by weight.

15. The composition of claim 14, wherein at least 85% by weight of the composition is comprised of long chain omega-3 fatty acids.

16. The composition of claim 15, wherein the EPA constitutes 40 to 60% by weight of the composition and the DHA constitutes 25 to 45% by weight of the composition.

17. The composition of claim 16, wherein C 20:4 omega-6 fatty acid constitutes at least one percent by weight of the composition.

18. The composition of claim 17, wherein C 22:5 omega-3 fatty acid constitutes at least one percent by weight of the composition.

19. The composition of claim 16, wherein the (all-Z omega-3) -6,9,12,15,18-he-neicosapentaenoic acid is present in an amount of from 1 to 4% by weight. 20. The composition of any of claims 17,18, or 19, wherein the EPA and DHA are present in an EPA:DHA weight ratio of from 1:1 to 2:1.

Asserted claim 40 is also a dependent claim, which refers back to independent claim 28, as follows.

28. A pharmaceutical mixed-fatty-acids composition in which

a) at least 80% by weight of the composition is comprised of a combination of (all-Z omega-3)-5,8,ll,14,17-eieosapentaenoic acid (EPA) and (all-Z omega-3)-4,7,10,13,16,19-docosahexaenoic acid (DHA) in a weight ratio of EPA:DHA of from 1:2 to 2:1 and

b) at least 3% by weight of the composition is comprised of omega-3 fatty acids other than EPA and DHA that have 20, 21, or 22 carbon atoms.

* * *

30. The composition of claim 28, wherein at least 85% by weight of the composition is comprised of long chain omega-3 fatty acids.

31. The composition of claim 30, wherein the EPA constitutes 40 to 60% by weight of the composition and the DHA constitutes 25 to 45% by weight of the composition.

* * *

38. The composition of claim 31, wherein (all-Z omega-3)-6,9,12,15,18-heneicosapentaenoic acid is present in an amount of at least one percent by weight.

40. The composition of claim 38, wherein the (all-Z omega-3)-6,9,12,15,18-heneicosapentaenoic acid is present in an amount of from 1 to 4% by weight.

Finally, claim 50, asserted against Teva, depends from claim 49, which reads:

49. A pharmaceutical mixed-fatty-acids composition in which

a) at least 90% by weight of the composition is comprised of long chain, polyunsaturated, omega-3 fatty acids;

b) at least 80% by weight of the composition is comprised of a combination of (all-Z omega-3)-5,8,ll,14,17-eicosapentaenoic acid (EPA) and (all-Z omega-3)-4,7,10,13,16,19-docosahexaenoic acid (DHA) in a weight ratio of EPA:DHA of from 1:1 to 2:1, with the EPA constituting 40 to 60% by weight of the composition and the DHA constituting 25 to 45% by weight of the composition;

c) at least 4.5% by weight of the composition is comprised of omega-3 fatty acids other than EPA and DHA that have 20, 21, or 22 carbon atoms;

d) from 1 to 4% by weight of the composition is comprised of (all-Z omega-3)-6,9,12,15,18-heneicosapentaenoic acid; and

e) the composition is in oral dosage form and includes an effective amount of a pharmaceutically acceptable antioxidant.

Claim 50 further requires that the fatty acids of the composition of claim 49 are present in ethyl ester form.

2. '077 patent

15. The '077 patent is related to the '667 patent; both patents are continuations of a common application (U.S. Patent Application No. 389,902 (“the '902 application”)) and, therefore, share the same specification. The '077 patent was filed on June 23, 1992 and issued March 26, 1996. As with the '667 patent, priority is claimed to August 11,1989.

16. Pronova asserts that defendants’ AND As infringe claim 9 of the '077 patent. Claim 9 is a dependent claim that incorporates the limitations of “any of [dependent] claims 5, 6 or 7,” and claims 5, 6 and 7 further depend on claims that reach back through their dependency to independent claim 1 of the '077 patent. Claim 1 reads as follows.

1. A method for the treatment or prophylaxis of hypertriglyceridemia in a human patient, which comprises orally administering to the patient a pharmaceutical composition in which the active ingredients consist essentially of a mixture of fatty acids of which at least 80% by weight is comprised of a combination of (all-Z omega-3)-5,8,ll,14,17-eicosapentaenoic acid (EPA) and (all-Z omega-3)~4,7,10,13,16,19-docosahexaenoie acid (DHA) in a weight ratio of EPA:DHA of from 1:2 to 2:1, said composition being administered in amounts providing a daily dosage of 1 to 10 grams of said mixture of fatty acids.

Each of claims 5-7 of the '077 patent incorporates the limitations of claim 4 which, in turn, incorporates the limitations of claim 3, and so on, through independent claim 1. Thus, by reason of its dependency, claim 9 contains the following additional limitations:

• at least 85% by weight of the mixture of fatty acids is comprised of long chain omega-3 fatty acids (dependent claim 2);

• the EPA constitutes 40 to 60% by weight of the mixture of fatty acids and the DHA constitutes 25 to 45% by weight of the mixture of fatty acids (dependent claim 3);

• the EPA and DHA are present in the composition in an EPA:DHA weight ratio of from 1:1 to 2:1 (dependent claim 4).

Additionally, at least one of the following limitations must also be present:

• at least 4.5% by weight of the mixture of fatty acids is comprised of fatty acids other than EPA and DHA that have 20, 21, or 22 carbon atoms (dependent claim 5);

• at least 3% by weight of the mixture of fatty acids is comprised of omega-3 fatty acids other than EPA and DHA that have 20, 21, or 22 carbon atoms (dependent claim 6)

• at least 1 % by weight of the mixture of fatty acids is comprised of (all-Z omega-3)-6,9,12,15,18-heneicosapentaenoic acid (dependent claim 7)

Finally, claim 9 itself requires that the fatty acids are present in the composition in ethyl ester form.

3. Claim summary

17. For ease of reference, the court reproduces below defendants’ chart summarizing the asserted claims’ requirements.

'077 Patent '667 Patent '667 Patent '667 Patent Composition of Claim 20 Claim 44 Claim 50 Claim 9

EPA + DHA at least 80% by weight ....

Ratio (at least 1:2 to 2:1 or 1:1 to 2:1) ....

40-60% EPA, 25-45% DHA_•_;_;_•

At least 3% other C20, C21 or C22 m-3_■_N/A_■_N/A

At least 4,5% other C20, C21 or C22 m-3_N/A_N/A_N/A_•

At least 1%C21:5(HPA)_•_•_N/A_N/A

From l%-4% C21:5 co-8 (HPA) N/A N/A N/A

At least 1% C22:5 m-3 (DPA) N/A N/A N/A

At least 1% C20:4 m-6 (AA) N/A • N/A N/A

At least 85%, 90% long chain w-3 ....

Ethyl Ester N/A

Oral Dosage Form • N/A N/A

Antioxidant (Tocopherol) N/A N/A N/A

(D.I. 209 at 24)

C. Claim Construction

1. Standards

18. Claim construction is a matter of law. Phillips v. AWH Corp., 415 F.3d 1303, 1330 (Fed.Cir.2005) (en banc). Claim construction focuses on intrinsic evidence — the claims, specification and prosecution history — because intrinsic evidence is “the most significant source of the legally operative meaning of disputed claim language.” Vitronics Corp. v. Conceptronic, Inc., 90 F.3d 1576, 1582 (Fed.Cir.1996); Markman v. Westview Instruments, Inc., 52 F.3d 967, 979 (Fed.Cir.1995) (en banc), aff'd, 517 U.S. 370, 116 S.Ct. 1384, 134 L.Ed.2d 577 (1996). Claims must be interpreted from the perspective of one of ordinary skill in the relevant art at the time of the invention. Phillips, 415 F.3d at 1313.

19. Claim construction starts with the claims, id. at 1312, and remains centered on the words of the claims throughout. Interactive Gift Express, Inc. v. Compuserve, Inc., 256 F.3d 1323, 1331 (Fed.Cir.2001). In the absence of an express intent to impart different meaning to claim terms, the terms are presumed to have their ordinary meaning. Id. Claims, however, must be read in view of the specification and prosecution history. Indeed, the specification is often “the single best guide to the meaning of a disputed term.” Phillips, 415 F.3d at 1315.

2. Intrinsic evidence

a. Specification

20. The abstracts of the patents-in-suit describe a “[flatty acid composition comprising at least 80% by weight of omega-3 fatty acids, salts or derivatives thereof[.]” (See '077 patent, abstract) The summary of the invention provides that

[i]t has now been found that fatty acid compositions containing a high concentration, of at least 80% by weight, of omega-3 fatty acids, salts or derivatives thereof, where EPA and DHA are present in relative amounts of 1:2 to 2:1, and constitute at least 75% of the total fatty acids, has a surprisingly advantageous effect on all the above mentioned risk factors for cardiovascular diseases, but especially a good effect on mild hypertension, hypertriglyceridemia and on the coagulation factor VII phospholipid complex activity....

{Id. at col. 2:50-58) The summary also provides that “[t]he analysis in % by weight was based on the ethyl esters even if other derivatives or salts or the acids themselves are part of the present invention.” {Id. at col. 3:16-19)

b. Prosecution history

21. As noted previously, the patents-in-suit issued from continuations of the '902 application; the court’s review of the relevant prosecution history begins there. Independent claim 1 of the '902 application was directed to a “[flatty acid composition comprising at least 80% by weight of omega-3 fatty acids” with specified relative amounts and weights for the EPA and DHA components. (D.I. 133 at JA-76) Dependent claims 7, 8 and 10 claimed compositions according to claim 1 “wherein the fatty acids are present in the form of pharmaceutically acceptable salts” (claim 7), “derivatives” (claim 8), or “ethyl esters” (claim 10). (Id. at JA-77) Dependent claim 9 depended from claim 8, and further required that “the derivative is an ester, especially an alkyl ester.” (Id.) These claims were rejected as obvious in view of three prior art references, including U.S. Patent No. 3,158,541 to Sutherland (“Sutherland”). (Id. at JA-150-53) After removal of the “especially” language of dependent claim 9 (and other amendments) (id. at JA-158), the examiner maintained the obviousness rejection, and made the rejection final. (Id. at JA-213-14)

22. Thereafter, the inventors cancelled claim 1 and added a new claim 19, claiming

[a] fatty acid composition for the treatment or prophylaxis of multiple risk factors for cardiovascular diseases, comprising at least 80% by weight of omega-3 fatty acids, whereof (all-Z)-5,8,ll,-14,17-eicosapentaeonic acid (EPA) C 20:5 and (all-Z)-4,7,10,13,16,19-docosahexaeonic acid (DHA) C 22:6 are present in relative amounts of from 1:2 to 2:1 and constitute at least 75% by weight of the total fatty acids.

(Id. at JA-228) Dependent claims 7 and 8 were amended to depend on new claim 19. (Id. at JA-229) The examiner maintained that the prior art disclosed pharmaceutical compositions containing eleanosanoic and docosahexanoic acid esters. (Id. at JA-232)

23. After a request for reconsideration, the examiner deemed further prosecution necessary, and issued a rejection of claims 7 to 10 as being: (1) “of improper dependent form for failing to further limit the subject matter of a previous claim;” and (2) “improperly dependent from claim 19 because claim 19 recites the acid, and claims 7 to 10 recite ‘derivatives,’ ‘salts,’ and ‘esters.’ ” (Id. at JA-239) The examiner also stated that the term “ ‘derivative(s)’ is vague and indefinite because it can mean amides, as well as salts and esters and other undefined derivatives.” (Id.)

24. Following a telephonic interview, the examiner noted that the “composition claims will be amended to include other omega fatty acids, and declarations will be presented to overcome the prior art.” (Id. at JA-244) The applicants proceeded to cancel claim 19 in favor of new claim 21, reciting:

21. A fatty acid composition for the treatment or prophylaxis of multiple risk factors for cardiovascular diseases, comprising at least 80% by weight of omega-3 fatty acids or pharmaceutically acceptable salts or other derivatives of said acids, whereof (all-Z)-5,8,ll,14,17eicosapentaeonic acid (EPA) C 20:5, or a pharmaceutically acceptable salt or other derivative of said acid, and (all-Z)-4,7,10,13,16,19-docosahexaeonic acid (DHA) C 22:6, or a pharmaceutically acceptable salt or other derivative of said acid, are present in relative amounts of from 1:2 to 2:1 and constitute at least 80% by weight of the total fatty acids or pharmaceutically acceptable salts or other derivatives of said acids, and omega-3 fatty acids other than said EPA and DHA are present in an amount of at least 1.5% by weight of the total fatty acids.

(Id. at JA-247) (emphasis added) The dependent claims were amended to depend from claim 21 (rather than 19). (Id. at JA-248) In their remarks, the applicants stated that,

[i]n view of the rejection of claims 7-10 under the fourth paragraph of 35 U.S.C. [§ ] 112, each of new claims 21 and 22[] recites pharmaceutically acceptable salts or other derivatives of the acids (in addition to the free acids as originally recited), thus rendering the rejection moot. The salts and derivatives are set forth in claims 7-10.

(Id. at JA-249) (emphasis added)

25. A final office action was then issued, in which the examiner maintained the § 103 rejection in view of Sutherland, and added an anticipation rejection based on a previously-cited obviousness reference. (Id. at JA-336) The examiner also maintained the § 112 rejection over the term “derivatives.” (Id. at JA-337) The examiner explained that the “[applicants argue that the term ‘derivatives’ is defined and claims stating ‘derivatives of fatty acids’ 'have been allowed in the past. However, in the instant specification, what the possible derivatives are have not been defined[J” (Id.)

26. In an amendment after final rejection, the applicants amended their claims to the esters of claim 9. (Id. at 359-60 (“Applicants have now decided to limit the derivatives to the esters.”)) On obviousness, a declaration was submitted which purported to demonstrate unexpected superior results of the DHA and EPA concentration of the invention. (Id. at JA-363) An advisory action was issued in which only the obviousness rejection in view of Sutherland was maintained by the examiner. (Id. at JA-382) After further prosecution, the applicants filed a notice of appeal, but ultimately abandoned the '902 application in favor of continuation application no. 07/902,500 (“the '500 application”), filed June 23, 1992. (Id. at JA-464-65, JA-468, JA-473-77) Also on June 23, 1992, a substitution of counsel was effected. (Id. at JA-478-49)

27. On November 18, 1992, then-pending claims 2-8, 10, 16-18, and 21-22 in the '500 application were rejected by the examiner. (Id. at JA-776-77) The claims remained rejected as obvious in view of Sutherland, and the examiner also stated with respect to § 112 that

[cjlaims 2 to 8, 21 and 22 are rejected ... as being indefinite.... The term “derivative” is unduly functional because the type of derivative has not been defined. Do applicants intend to include heavy metal salts and amides?

(Id. at JA-779)

28. In response, the applicants noted confusion over the rejection given that “the word ‘derivative’ did not appear in any of those claims[.]” (Id. at JA-828) Notwithstanding, the applicants cancelled all pending claims and substituted new claims 23-78, which also did not utilize the term “derivative.” (Id.) New claim 23 read as follows:

23. A mixed-fatty-acids composition for the treatment or prophylaxis of multiple risk factors for cardiovascular diseases in which

a) at least 80% by weight of the composition is comprised of omega-3 fatty acids,

b) at least 80% by weight of the total fatty acid content of the composition is comprised of a combination of (all-Z omega-3)-5,8,ll,14,17-eieosapentaeonic acid (EPA) and (all-Z)^,7,10,13,16,19docosahexaeonic acid (DHA) in a weight ratio of EPA:DHA of from 1:2 to 2:1, and

c) omega-3 fatty acids other than EPA and DHA are present in an amount of at least 1.5% by weight of the total fatty acids.

(Id. at JA-803-04) New dependent claims further required that “the fatty acids are present in the form of pharmaceutically acceptable salts” (claim 29), “an ester” (claim 30), and “ethyl esters” (claim 31). (Id. at JA-805) New independent claim 34 was also added, and claimed as follows:

34. A mixed-fatty-acids composition for the treatment or prophylaxis of multiple risk factors for cardiovascular diseases in which

a) at least 80% by weight of the composition is comprised of a combination of (all-Z omega-3)-5,8,ll,14,17-eicosapentaeonic acid (EPA) and (all-Z)-4,7,10,-13,16,19-docosahexaeonicacid (DHA) in a weight ratio of EPA:DHA of from 1:2 to 2:1 and

b) (all-Z omega-3)-6,9,12,15,18-heneicosaptentaeonic acid is present in an amount of at least one percent by weight.

(Id. at JA-806-07) New dependent claims 45-48, which depended from 24 or 34, further required that “the fatty acids are present in esterified form” (claim 45), “ethyl ester form” (claim 46), “salt form” (claim 47) and “free acid form” (claim 48). (Id. at JA-807-09)

29. As is custom, the applicants identified the support for their new claims in the specification, noting the locations of disclosure of the “use of the acids in esterified form,” “ethyl ester form,” “salt form” and the “free acid form.” (Id. at JA-818) With respect to the lingering obviousness rejection based on Sutherland, the applicants noted, inter alia, that Sutherland teaches “the use of a mixed-fatty-acids composition” to treat hypercholesterolemia and “places no emphasis on any particular fatty acids[.]” (Id. at JA-819) Further, the applicants argued that “[a]ll of the present claims (23-78) differ from Sutherland in at least one particular [way]: They specify that at least 80% of the fatty acid content is comprised of a combination of EPA and DHA.” (Id. at JA-820)

30. Subsequently, the applicants presented new claims 79-105 for prosecution. Independent claim 94 would eventually issue, unchanged, as claim 1 of the '077 patent. The claim reads:

A method for the treatment or prophylaxis of hypertriglyceridemia in a human patient, which comprises orally administering to the patient a pharmaceutical composition in which the active ingredients consist essentially of a mixture of fatty acids of which at least 80% by weight is comprised of a combination of (all-Z omega-3)-5,8,ll,14,17-eicosapentaenoic acid (EPA) and (all-Z omega-3)-4,7,10,13,16,19-docosahexaenoic acid (DHA) in a weight ratio of EPA:DHA of from 1:2 to 2:1, said composition being administered in amounts providing a daily dosage of 1 to 10 grams of said mixture of fatty acids.

31. In a subsequent office action, the examiner rejected the pending claims as anticipated and as obvious in view of U.S. Patent No. 5,130,611 to Cornieri et ah, disclosing at least a 69% mixture of EPA and DHA. (Id. at JA-989) After further prosecution, claims 94-105 were deemed allowable in view of evidence showing improved results in the treatment of hypertriglyceridemia. (Id. at JA-1049) The applicants canceled the remaining claims (id. at JA-1052) and the '500 application was allowed as the '077 patent (id. at JA-1058).

3. Discussion

32. Of pivotal import in this case is the court’s construction of the term “fatty acid” as used in the claims of the '077 and '667 patents. The issue presented, specifically, is whether “fatty acid” includes free fatty acids, salts and derivatives such as esters.

33. The intrinsic evidence supports defining “fatty acids” as broader than “free acids” or “omega-3 fatty acids,” as used in the claims. The structure of the claims of the '902 application support this broad interpretation of “fatty acids,” insofar as the dependant claims required that “the fatty acids are present in the form of’ derivatives, esters or salts. (D.I. 133 at JA-77) Claim 19 also used the term “total fatty acids” to signify a broader class of compounds than “omega-3 fatty acids,” which subgroup further includes EPA and DHA. Similar terminology was also repeated in '500 application claims 23 (“total fatty acids”) and the dependent claims 24 or 34 (e.g., “the fatty acids are present in esterified form”). (Id. at JA-804, JA-807-09) Consequently, there is a presumption that “fatty acids” should be construed broadly. See gen., Marine Polymer Techs., Inc. v. HemCon, Inc., 672 F.3d 1350, 1368 (Fed.Cir.2012) (“Where a particular construction of an independent claim would nullify claims that depend from it, the doctrine of claim differentiation creates a presumption that such a construction is improper.”) (citing Liebel-Flarsheim Co. v. Medrad, Inc., 358 F.3d 898, 910 (Fed.Cir.2004)).

34. In arguing for a narrow construction, defendants emphasize that the examiner rejected claims 7 to 10 of the '902 application for improper dependency because “claim 19 recites the acid, and claims 7 to 10 recite ‘derivatives,’ ‘salts,’ and ‘esters.’ ” (D.I. 119 at 7 (citing D.I. 133 at JA-239)) Claim 19 was drawn to a fatty acid composition comprising at least 80% “omega-3 fatty acids” where EPA and DHA is present in “at least 75% by weight of the total fatty acids.” (D.I. 133 at JA-228) The examiner’s primary concern was with the vagueness and redundancy of the term “derivative,” and required that the claims “be amended to include other fatty acids.” (Id. at JA-244) (emphasis added) The applicants cured the dependency by amending the independent claim to require at least 80% “omega-3 fatty acids or pharmaceutically acceptable salts or other derivatives of said acids,” ergo, specific derivatives of “the [omega-3] free acids as originally recited.” (Id. at JA-244, JA-248^49) (emphasis added) Later, the concern over “derivatives” was mooted by the applicants’ selection of esters.

35. The foregoing supports a broad construction of “fatty acids,” as the addition of “pharmaceutically acceptable salts or other derivatives of said [omega-3 fatty] acids” appears to have satisfied the examiner’s request to amend the claims to include “other fatty acids.” Where the specification distinguishes between the terms, it does so in the context of “omega-3 fatty acids” rather than “fatty acids” absent any qualifying terms. (’077 patent, col. 3:16-18; see also id. at abstract, col. 2:52 (“omega-3 fatty acids, salts or derivatives thereof’) (emphasis added)) There is no clear disclaimer vis-a-vis “fatty acids,” as was used in the “total fatty acids” limitation in claims 21 or 23 of the '500 application, or “fatty acids” as used in claim 94 (issuing as claim 1 of the '077 patent).

36. The court does not find defendants’ evidence sufficient to rebut the presumption established by claim differentiation. See Marine Polymer Techs., 672 F.3d at 1368 (construction of a term which renders claims meaningless is appropriate “only where a contrary construction is ‘dictated’ — i.e., compelled — by the written description or prosecution history”) (citations omitted).

37. The court also notes extrinsic evidence consistent with its finding, as follows. Scientific and medical dictionaries customarily define a “fatty acid” broadly. See McGraw-Hill Dictionary of Scientific and Technical Terms 780 (6th ed.2003) (“[a]n organic monobasic acid of the general formula CnH2n+1COOH derived from the saturated series of aliphatic hydrocarbons”); Dorland’s Illustrated Medical Dictionary 693 (31st ed.2007) (“any straight chain monocarboxylic acid, especially those naturally occurring in fats”); see also Alan W. Cuthbert, Fats, The Oxford Companion to the Body (Colin Blake-more and Shiela Jennett, ed., Oxford University Press 2001) (describing fatty acids as “long chains of carbon atoms linked to a carboxyl (acidic) group”).

38. For the foregoing reasons, the court declines to limit “fatty acids” to the free fatty acid, ester or salt form as advocated by defendants, nor does the court find “fatty acids” to be indefinite, as asserted by defendants. (D.I. 209 at 44) Having declined to adopt defendants’ construction, the court also declines to find the dependent claims of the '077 and '667 patents invalid for improper dependency under § 112, ¶ 4. (Id. at 43-44)

D. Infringement

1. Standards

39. A patent is infringed when a person “without authority makes, uses or sells any patented invention, within the United States ... during the term of the patent.” 35 U.S.C. § 271(a). A two-step analysis is employed in making an infringement determination. See Markman v. Westview Instruments, Inc., 52 F.3d 967, 976 (Fed.Cir.1995). First, the court must construe the asserted claims to ascertain their meaning and scope. See id. Construction of the claims is a question of law subject to de novo review. See Cybor Corp. v. FAS Techs., 138 F.3d 1448, 1454 (Fed.Cir.1998). The trier of fact must then compare the properly construed claims with the accused infringing product. See Markman, 52 F.3d at 976. This second step is a question of fact. See Bai v. L & L Wings, Inc., 160 F.3d 1350, 1353 (Fed.Cir.1998).

40. “Direct infringement requires a party to perform each and every step or element of a claimed method or product.” BMC Res., Inc. v. Paymentech, L.P., 498 F.3d 1373, 1378 (Fed.Cir.2007). “If any claim limitation is absent from the accused device, there is no literal infringement as a matter of law.” Bayer AG v. Elan Pharm. Research Corp., 212 F.3d 1241, 1247 (Fed.Cir.2000). If an accused product does not infringe an independent claim, it also does not infringe any claim depending thereon. See Wahpeton Canvas Co. v. Frontier, Inc., 870 F.2d 1546, 1553 (Fed.Cir.1989). However, “[o]ne may infringe an independent claim and not infringe a claim dependent on that claim.” Monsanto Co. v. Syngenta Seeds, Inc., 503 F.3d 1352, 1359 (Fed.Cir.2007) (quoting Wahpeton Canvas, 870 F.2d at 1552) (internal quotations omitted). A product that does not literally infringe a patent claim may still infringe under the doctrine of equivalents if the differences between an individual limitation of the claimed invention and an element of the accused product are insubstantial. See Warner-Jenkinson Co. v. Hilton Davis Chem. Co., 520 U.S. 17, 24, 117 S.Ct. 1040, 137 L.Ed.2d 146 (1997). The patent owner has the burden of proving infringement and must meet its burden by a preponderance of the evidence. See SmithKline Diagnostics, Inc. v. Helena Lab. Corp., 859 F.2d 878, 889 (Fed.Cir.1988) (citations omitted).

41. Under 35 U.S.C. § 271(b), “[w]hoever actively induces infringement of a patent shall be liable as an infringer.” To demonstrate inducement of infringement, the patentee must establish, first, that there has been direct infringement and, second, that the alleged infringer had “knowledge that the induced acts constitute patent infringement.” Global-Tech Appliances, Inc. v. SEB S.A., — U.S. —, 131 S.Ct. 2060, 2068, 179 L.Ed.2d 1167 (2011). “Inducement requires evidence of culpable conduct, directed to encouraging another’s infringement, not merely that the inducer had knowledge of the direct infringer’s activities.” DSU Medical Corp. v. JMS Co., Ltd., 471 F.3d 1293, 1306 (Fed.Cir.2006) (en banc in relevant part).

42. Under 35 U.S.C. § 271(c), a patentee must demonstrate that an alleged contributory infringer has sold, offered to sell or imported into the United States a component of an infringing product “knowing the same to be especially made or especially adapted for use in an infringement of such patent, and not a staple article or commodity of commerce suitable for substantial noninfringing use.” Therefore, § 271(c) “require[s] a showing that the alleged contributory infringer knew that the combination for which [its] component was especially designed was both patented and infringing.” Aro Mfg. Co. v. Convertible Top Replacement Co., 377 U.S. 476, 488, 84 S.Ct. 1526, 12 L.Ed.2d 457 (1964).

2. Discussion

43. There is no dispute that defendants’ ANDA products are composed of fatty acid ethyl esters (“FAEEs”). Defendants’ only noninfringement argument occurs under their proposed construction of “fatty acids” as excluding FAEEs. (D.I. 214)

44. Notwithstanding, as Pronova had the burden to prove infringement by a preponderance of the evidence, the court notes that it found convincing Pronova’s evidence of infringement. Pronova presented testimony by Dr. Jonathan Curtis (“Curtis”), an associate professor in the analytical lipid chemistry group at the University of Alberta, Department of Agriculture, Food and Nutritional Sciences, and an expert in analytical chemistry and the quantitative analysis of fish oil. The court also heard testimony by Dr. John Kane (“Kane”), Professor of Medicine at the University of California, San Francisco, Associate Director of the Cardiovascular Research Institute and Director of the Genomic Resource in Arteriosclerosis and Metabolic Disease, and an expert in the fields of lipid biology and lipid disorders.

45. Curtis compared Teva’s ANDA product to the asserted claims and concluded that Teva’s ANDA product directly infringes the asserted claims of the '667 patent and meets the composition limitations of the asserted claims of the '077 patent. (D.I. 200 at 65:10-19, 74:10-92:22; PTX-1240A (summary of supporting exhibits)) Curtis also compared Par’s ANDA product to the asserted claims and concluded that Par’s ANDA product will directly infringe the asserted claims of the '667 patent, and that Par’s ANDA product will meet the composition limitations of the asserted claims of the '077 patent. (D.I. 201 at 129:8-137:15; PTX-1242A (summary of supporting exhibits))

46. With respect to indirect infringement, defendants’ labels indicate that then-products are intended for oral administration. (PTX-331 at TOMEG0005250; PTX-516 at PAR00004813^814) Kane testified that Teva and Par’s prescribing information for their generic products indicate that each is intended to be used to treat hypertriglyceridemia in patients with triglyceride levels of greater than or equal to 500 mgklL and, thus, the proposed indications of defendants’ generic products are encompassed by the claim language of “a method for the treatment or prophylaxis of hypertriglyceridemia in a human patient.” (D.I. 201 at 162:3-164:3, 165:10-166:2) Furthermore, as physicians are expected to follow prescribing information, defendants’ proposed prescribing information would instruct physicians on how to use Teva’s and Par’s generic products in the same way as Lovaza®. (Id. at 166:9-167:7) Defendants conducted no cross examination of Dr. Kane and presented no rebuttal evidence in their case-in-chief.

47. The court finds plaintiffs infringement evidence credible and, for the above reasons, concludes that defendants’ ANDA products infringe the patents-in-suit.

E. Anticipation

The court next addresses defendants’ argument that the asserted composition claims (of the '677 patent) are invalid for public use before the statutory bar date.

48. There is no dispute between the parties that, on September 8, 1987, Norsk Hydro sent Dr. Victor Skrinska (“Skrinska”), then-director of biochemistry research within the cardiovascular research group at the Cleveland Research Institute, liquid vials of “K-80” ethyl esters from Batch No. 222. (D.I. 209 at 35; D.I. 215 at 43; DTX-81A; DTX-82; DTX-83; DTX-84; DTX-85; DTX-86) Pronova does not contest that the Batch 222 samples meet all of the claimed limitations, as they contained 86.5 by weight EPA EE + DHA EE (53.2% by weight EPA, 33.3% by weight DHA), as well as the other omega-3 and omega-6 fatty acids and Vitamin E (as an antioxidant) recited in the asserted claims. (D.I. 209 at 35 (citing DTX-86; D.I. 203 at 698:3-699:12; D.I. 202 at 483:24^84:6; D.I. 204 at 743:24-748:19); D.I. 215 at 43-47)

49. Defendants contend that

Norsk Hydro made commercial public use of its product by disclosing its contents and providing product samples to, among others, Dr. Skrinska. Dr. Skrinska made public use of the Skrinska material by testing to confirm its contents and discussing it with colleagues. In addition, Dr. Skrinska made further public use of the Skrinska material by administering capsules to himself and others. No confidentiality agreement restricted these public uses.

(D.I. 209 at 34) Pronova argues that there is no corroborating evidence to support Skrinska’s testimony about using the samples in a study or for any other purpose. (D.I. 215 at 43-47)

50. Defendants also point to the following shipments as preceding invalidating public uses by the recipients: (1) shipments of “K80” to Dr. Fran Peterson (“Peterson”) of General Mills on February 17, 1987; (2) shipments of 1000 capsules of “K85” to Professor Arne Nordpy (“Nordpy”) at the University of Oregon in January 1988; and (3) shipments of samples of “K80” to Professor Roger Davis (“Davis”) at the University of Colorado in January 1988. (D.I. 209 at 38 (citing DTX-99, DTX-150, DTX-113 and DTX-114))

1. Public use standard

51. Public use under 35 U.S.C. § 102(b) includes any use of the claimed invention by a person other than the inventor who is under no limitation, restriction or obligation of secrecy to the inventor. Whether a patent is invalid due to a § 102(b) public use is a question of law based on underlying questions of fact.

Minnesota Min. & Mfg. Co. v. Chemque, Inc., 303 F.3d 1294, 1301-02 (Fed.Cir.2002) (internal citations omitted).

2. Discussion

a. Work by Nordpy

52. Pronova does not contest that it sent 1000 capsules of “K85” to Nordpy in January 1988 for study. (D.I. 215 at 47) Rather, it notes that Nord0y conducted an experimental bioavailability study that was detailed to the PTO during prosecution of the '667 and '077 patents. (Id. (citing PTX-9 at PRV409076-86, PRC409089-123, PRV407448-55; PTX-10 at PRV40744855)) Additionally, Pronova argues that defendants waived this argument because it was not raised in discovery or in the pretrial order. (Id.) Defendants do not attempt to rebut Pronova’s evidence in these regards in their reply papers. (D.I. 218 at 18-22) The court does not invalidate the '667 or '077 patents on the basis of Nord0y’s work.

b. Peterson and Davis

53. While Pronova does not contest that K80 was shipped to Peterson and Davis in 1987 and 1988, respectively, Pro-nova also (correctly) points out that defendants do not point to any evidence that those samples were ever used. (D.I. 215 at 18, 43) Defendants emphasize testimony by Norsk Hydro’s former business development manager that his role was to contact companies and determine potential medical markets for drug samples. (D.I. 209 at 39 (citations omitted)) As defendants’ cited evidence does not demonstrate that Peterson, Davis or others actually used the samples they received, the court does not find defendants’ evidence of invalidity clear and convincing in this regard,

c. Skrinska

54. The documents demonstrate that Skrinska was sent two, lOOmL samples of Batch 222 on September 8, 1987, with a specification sheet. (DTX-84, DTX-85, DTX-86) There are no confidentiality concerns or other mentions of the potential uses in the cover letter accompanying the liquid samples. (Id.) Pronova does not identify any such restrictions in its answering papers. (D.I. 215 at 42-47)

55. The pivotal question is whether Skrinska actually used “the claimed invention” and, if so, in what manner. See id. at 1307 (“Although there is evidence in the record that samples of Ricoseal were sent to various corporations, there is no [direct] evidence of their use”) (declining to invalidate based on anticipation). “Although ‘public use’ for purposes of § 102(b) is defined differently from ‘use’ for purposes of § 102(a), both require actual use by someone at some point.” Id.

56. As to this issue, Skrinska testified that he tested the amounts of fatty acids within these two samples and found that the certificate of analysis supplied by Norsk Hydro was correct. (D.I. 202 at 483:24-484:6) Defendants do not point to any particular “use” of the two Batch 222 liquid vials.

57. Skrinska further testified that he “believe[s]” that Norsk Hydro sent him “maybe 500 to 1000 capsules [of concentrated fish oil] to do some studies.” (D.I. 202 at 477:10-17, 485:16-25) He could not remember whether he ever received any fish oil capsules from anyone besides Norsk Hydro. (Id. at 480:8-20) He could also not remember any specific data from assays on the capsules, although Skrinska recalled that they were in conformity with the previous samples. (Id. at 484:7-16) Skrinska stated that six volunteers were selected from the Cleveland Research Institute staff for a study using the Norsk Hydro capsules (including himself as one of the volunteers), which study involved taking “approximately six capsules a day for two weeks,” and after which they looked at fatty acid composition in the membranes of platelets. (Id. at 484:25-485:15) Skrinska recorded the results of this study in a notebook, although no one from Norsk Hydro asked to see the results of the study, and he did not send them any data. (Id. at 486:1-22) Skrinska testified that “everyone related to the Cleveland Research Institute was aware of what [they] were doing through just regular meetings and updates,” including the board members, and they also “freely exchange^] information at conferences and with colleagues” in the field. (Id. at 493:4-14)

58. Defendants proffer no corroborating documentary evidence for these extensive claims, for example, Skrinska’s notebooks, proposals, meeting minutes, or conference documentation. The only documentary evidence cited with respect to Skrinska’s activities are two letters. The first is from Dr. Irene Wei (‘Wei”), assistant professor of medicine at Case Western Reserve University School of Medicine, to Sigurd Gulbrandsen at Norsk Hydro. In this communication, Wei states that she learned “of the existence of your concentrated product of omega-3 fatty acids (80%) as ethyl esters” from Skrinska, a colleague. (DTX-111) Wei asks for more information about the product and literature related to its clinical usage. (Id.) The other letter is addressed to Wei and Dr. John Sheehan, M.D. of the Diabetes Management Center of Case Western Reserve University from Dr. Hans Krokan, M.D. (“Krokan”) at Norsk Hydro. (DTX-112) Therein, Krokan responds to Wei’s request for information and references Norsk Hydro’s present work on K85, including (not yet published) clinical studies. (Id.) Krokan states that it is “likely that we can supply you with capsules or oil” but requests more information on “how the preparations are to be used before reaching a final decision.” (Id.)

59. The court found Skrinska’s generalized testimony (twenty years after the fact) less than compelling; the foregoing is insufficient to corroborate Skrinska’s testimony regarding the purported invalidating public “uses.” See Minnesota Mining & Mfg. Co., 303 F.3d at 1307; see also Finnigan Corp. v. International Trade Com’n, 180 F.3d 1354, 1369 (Fed.Cir.1999) (“[Corroboration is required of any witness whose testimony alone is asserted to invalidate a patent, regardless of his or her level of interest”). As discussed above, the court does not find persuasive defendants’ evidence that Norsk Hydro was shopping K80 and/or K85 in the market, as this evidence is not indicative of any actual prior public “use” of the invention as claimed. For the foregoing reasons, the court does not invalidate either the '667 or '077 patent on public use grounds.

F. Obviousness

1. Standards

60. “A patent may not be obtained ... if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art.” 35 U.S.C. § 103(a). Obviousness is a question of law, which depends on underlying factual inquiries.

Under § 103, the scope and content of the prior art are to be determined; differences between the prior art and the claims at issue are to be ascertained; and the level of ordinary skill in the pertinent art resolved. Against this background the obviousness or nonobviousness of the subject matter is determined. Such secondary considerations as commercial success, long felt but unsolved needs, failure of others, etc., might be utilized to give light to the circumstances surrounding the origin of the subject matter sought to be patented.

KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 406, 127 S.Ct. 1727, 167 L.Ed.2d 705 (2007) (quoting Graham v. John Deere Co., 383 U.S. 1, 17-18, 86 S.Ct. 684, 15 L.Ed.2d 545 (1966)).

61. “[A] patent composed of several elements is not proved obvious merely by demonstrating that each of its elements was, independently, known in the prior art.” KSR, 550 U.S. at 418, 127 S.Ct. 1727. Likewise, a defendant asserting obviousness in view of a combination of references has the burden to show that a person of ordinary skill in the relevant field had a reason to combine the elements in the manner claimed. Id. at 418-19, 127 S.Ct. 1727. The Supreme Court has emphasized the need for courts to value “common sense” over “rigid preventative rules” in determining whether a motivation to combine existed. Id. at 419-20, 127 S.Ct. 1727. “[A]ny need or problem known in the field of endeavor at the time of invention and addressed by the patent can provide a reason for combining the elements in the manner claimed.” Id. at 420, 127 S.Ct. 1727. In addition to showing that a person of ordinary skill in the art would have had reason to attempt to make the composition or device, or carry out the claimed process, a defendant must also demonstrate that “such a person would have had a reasonable expectation of success in doing so.” PharmaStem Therapeutics, Inc. v. ViaCell, Inc., 491 F.3d 1342, 1360 (Fed.Cir.2007).

62. A combination of prior art elements may have been “obvious to try” where there existed “a design need or market pressure to solve a problem and there [were] a finite number of identified, predictable solutions” to it, and the pursuit of the “known options within [a person of ordinary skill in the art’s] technical grasp” leads to the anticipated success. Id. at 421, 127 S.Ct. 1727. In this circumstance, “the fact that a combination was obvious to try might show that it was obvious under § 103.” Id. Federal Circuit precedent has also established that “[s]tructural relationships may provide the requisite motivation or suggestion to modify known compounds to obtain new compounds,” and that particular types of structural similarity can give rise to a case of prima facie obviousness. Genetics Institute, LLC v. Novartis Vaccines and Diagnostics, Inc., 655 F.3d 1291, 1312 (Fed.Cir.2011) (citing In re Deuel, 51 F.3d 1552, 1558 (Fed.Cir.1995)).

63. A court is required to consider secondary considerations, or objective indicia of nonobviousness, before reaching an obviousness determination, as a “check against hindsight bias.” See In re Cyclobenzaprine Hydrochloride Extended-Release Capsule Patent Litig., 676 F.3d 1063, 1079 (Fed.Cir.2012). “Such secondary considerations as commercial success, long felt but unsolved needs, failure of others, etc., might be utilized to give light to the circumstances surrounding the origin of the subject matter sought to be patented.” Graham v. John Deere Co. of Kansas City, 383 U.S. 1, 17-18, 86 S.Ct. 684, 15 L.Ed.2d 545 (1966).

64. “Because patents are presumed to be valid, see 35 U.S.C. § 282, an alleged infringer seeking to invalidate a patent on obviousness grounds must establish its obviousness by facts supported by clear and convincing evidence.” Kao Corp. v. Unilever U.S., Inc., 441 F.3d 963, 968 (Fed.Cir.2006) (citation omitted). In conjunction with this burden, the Federal Circuit has explained that,

[w]hen no prior art other than that which was considered by the PTO examiner is relied on by the attacker, he has the added burden of overcoming the deference that is due to a qualified government agency presumed to have properly done its job, which includes one or more examiners who are assumed to have some expertise in interpreting the references and to be familiar from their work with the level of skill in the art and whose duty it is to issue only valid patents.

PowerOasis, Inc. v. T-Mobile USA, Inc., 522 F.3d 1299, 1304 (Fed.Cir.2008) (quoting Am. Hoist & Derrick Co. v. Sowa & Sons, 725 F.2d 1350, 1359 (Fed.Cir.1984)).

2. Composition claims

65. Defendants summarize their obviousness position as follows.

The prior art disclosed at least five concentrated fish oil compositions containing 80% or higher (“>80%”) EPA + DHA, including EE species, in a 1:2 to 2:1 ratio of EPA:DHA, having the minor components, and including compositions with antioxidant and in an oral dosage form. In addition, at least five other prior art references disclosed concentrates containing between 70-80% EPA + DHA. The unrebutted trial record is that this prior art both (1) disclosed the claimed compositions to a [person of ordinary skill in the art (“POSA”) ] and (2) provided a POSA with everything necessary to make the claimed compositions: (i) starting material [ ]; (ii) target percentages of >80% EPA + DHA [ ]; (ii) motivation to make very concentrated compositions; (iv) the techniques to prepare such compositions; and (v) a reasonable expectation that the resulting concentrate would meet all of the claim limitations, including the limitations relating to the minor components.

(D.I. 209 at 24) (internal citations omitted). In support, defendants cite to their expert, Dr. Bruce Ganem (“Ganem”), who identified five asserted prior art references published before August 4, 1988 and describing omega-3 compositions having 80% by weight of EPA and DHA in the 1:2-2:1 ratio: (1) a paper entitled “Purification of Omega-3 Fatty Acids from Fish Oils using HPLC: An Overview” by Judith Krzynowek et al. (“Krzynowek”) (DTX-699); (2) an abstract entitled “Compared Absorption of Marine Fatty Acids in Humans after Two Weeks Oral Intake of a Triglyceride or an Ethylester Concentrate” by inventor Knut Dahl et al. (the “Dahl abstract”) (DTX-137A); (3) Batch 222 vials and capsules sent to Skrinska, as discussed supra (DTX-80-86) (“the Skrinska material”); (4) a publication entitled “Study of Perinatal and Postnatal Effects in Rats After Oral Administration of a New Drug Containing Eicosapentaenoic Acid and Docosahexaenoic Acid at 85%” by M. De Bernardini et al. (“De Bernardini”) (DTX-1429); (5) international patent application (PCT) no. WO 87/03899, entitled “A Refined Fish Oil Concentrate and the Production Process for Sample,” naming Harald Breivik et al. as inventors (“Brevik”) (DTX-177). (D.I. 204 at 734:10-735:14 (cited at D.I. 209 at 24))

66. Defendants’ argument in their post-trial papers does not mirror this cited testimony. Defendants assert that a skilled artisan could have readily started with fish oil manufactured by the NMFS (at least 70% by weight of EPA EE + DHA EE in a 1:1 to 2:1 ratio), and adopted a target percent of EPA + DHA over 80% from Krzynowek, De Bernardini, Skrinska or Dahl. (D.I. 209 at 24-25)

67. It is not abundantly clear what disclosures (or uses) by the NMFS constitute prior art. In describing the NMFS compositions, defendants cite the testimony of inventor Dahl and its expert Galem that the NMFS had compositions available for use. (D.I. 209 at 12) -In connection with their obviousness argument, defendants rely on the Krzynowek, Joseph, Nilssen, Brevik and De Bernardini prior art references. (Id. at 24-26) That is, a skilled artisan would have started with the 88% EPA EE + DHA EE composition disclosed in Krzynowek, or the 85% EPA EE + DHA EE composition disclosed in De Bernardini, added tocopherol (an antioxidant) and prepared an oral dosage form. (D.I. 209 at 25-26) Alternatively, a skilled artisan could have started with an EPA + DHA composition lower than the claimed 80% by weight from various sources (including Breivik, at 75-77%) and “readily concentrated” them. (D.I. 209 at 25) Defendants describe in detail three separation methods which were well-known in the art for concentrating EPA, DHA and other omega-3 fatty acids: distillation, urea fractionation, and supercritical fluid extraction. (D.I. 209 at 9-12)

68. Having considered all of the proffered evidence of obviousness, as well as the secondary indicia of nonobviousness proffered by Pronova and defendants’ counterevidence, the court finds that defendants have failed to meet their burden to prove invalidity by clear and convincing evidence for the following reasons. Even if the court were to accept that >80% EPA EE + DHA EE was disclosed in, or readily produceable according to, the prior art, defendants do not sufficiently address the asserted claims as a whole. As defendants’ chart illustrates (supra pp. 509-10), the claims are directed to unique mixed-fatty-acid compositions that include, among other limitations, a specific combination of omega-3 and omega-6 fatty acids, other than just EPA and DHA, in particular amounts. There is no separate discussion of the composition included within '077 patent claim 9 or the composition that is the subject of '667 patent claims 20, 44 or 50, and there is no detailed comparison of the prior art compositions to the full scope of the claimed inventions.

69. The components other than EPA and DHA are grouped together by defendants in what they call “minor components.” (D.I. 209 at 28-29) Defendants point to testimony by their expert, Dr. Syed Rizvi (“Rizvi”), Professor of Food Process Engineering at Cornell University, that: (1) a person of ordinary skill in the art would recognize that the process described in Joseph would “preserve! ] and concentrate! ]” the remaining 12% components present in the original menhaden oil (DPA, HPA and AA); and (2) Nilsson’s PUFA2 sample (obtained from NMFS) contained “each of the minor components,” and those less than 1% would be concentrated during the process. (Id. (citing D.I. 204 at 908:13-910:5) (concluding that the minor components “should be preserved”), 916:13-920:25) Defendants broadly conclude that “!t]he same would be true for any of the prior art compositions.” (Id. at 29)

70. The foregoing is insufficient evidence to support a conclusion that each of the composition claims, containing particular combinations of C20, C21 or C22 omega-3 acids, HPA, DPA, AA, long chain omega-3 acids, EE, and antioxidant in particular concentrations in addition to EPA and DHA, are obvious in view of the cited prior art. There is no particular articulated motivation to combine the asserted references in the specific manners claimed, or a reasonable expectation of success in doing so. These omissions are especially troublesome given that Pronova provided credible evidence that concentrating the NMFS test materials would have been contrary to concerns of artisans at the time about potential detrimental effects of fish oils, such as adverse increases in LDL cholesterol levels. (D.I. 203 at 600:7-607:3; PTX-1083; PTX-1080; PTX-1078; D.I. 204 at 955:6-956:23; DTX-938-R)

71. As a final matter, the court notes (and rejects) defendants’ argument that the Skrinska materials render the composition claims obvious for the same reasons discussed with respect to anticipation. (D.I. 209 at 26) Defendants did not meet their burden to demonstrate a prior public use of Batch 222, ending that inquiry.

72. Having found that defendants have not demonstrated obviousness of the composition claims by clear and convincing evidence, the court declines to hold claim 9 of the '077 patent (claiming a method of treatment of hypertr