ViiV Healthcare UK Ltd. v. Lupin Ltd. (6 F. Supp. 3d 461, 2013)

United States District Court for the District of Delaware 2013-12-17

Citations

Full opinion text

TRIAL OPINION

ANDREWS, UNITED STATES DISTRICT JUDGE:

Plaintiffs ViiV Healthcare UK Ltd. and ViiV Healthcare Co. (collectively “ViiV”) assert U.S. Patent No. 6,417,191 (“the '191 Patent”) against Defendants Teva Pharmaceuticals, Inc. (“Teva”), Lupin Ltd., and Lupin Pharmaceuticals, Inc. (collectively “Lupin”). The '191 Patent (JX 1) is titled “Synergistic Combinations of Zidovudine, 1592U89 and 3TC.” (D.I.178, Ex. 1 ¶ 7). The patent issued on July 9, 2002, and expires on March 28, 2016. (Id. ¶¶ 7, 9). The named inventors are David Walter Barry and Martha Heider St. Clair. Id. ¶ 8. The patent claims recite formulations and methods of treating HIV infection, using (a) the “triple combination” of abaca-vir, zidovudine, and 3TC; or (b) the “double combination” of abacavir and 3TC. (JX 1 cols. 12-16).

ViiV holds NDA No. 21-205 for Trizivir, an oral tablet dosage form, which the FDA approved in November 2000 as an HIV drug. (D.I. 178, Ex. 1 ¶¶ 13-15). Trizivir contains the “triple combination” of abaca-vir, 3TC, and AZT. ViiV also holds NDA No. 21-652 for an oral tablet dosage form for Epzicom, which the FDA approved in August 2004 as an HIV drug. (Id. ¶ 20). Epzicom contains the “double combination” of abacavir and 3TC. The FDA’s Orange Book lists ViiV’s '191 Patent in connection with both products. (Id. ¶¶ 16, 23). ViiV’s case against Teva and Lupin arises out the Defendants’ ANDA filings with the FDA. Teva seeks FDA approval to market a generic version of Epzicom, while Lupin seeks FDA approval for a generic version of Trizivir. (Id. ¶ 17).

Defendants assert that the '191 Patent is invalid as obvious. Lupin individually asserts that the '191 Patent is invalid due to lack of enablement and utility, and also asserts that its proposed generic product does not infringe the '191 Patent. The Court held a four and a half day bench trial on June 24, 25, 26, 27, and 28. Defendants failed to prove any of their invalidity defenses by clear and convincing evidence, while ViiV failed to prove that Lupin’s generic drug product infringes the asserted claims of the '191 Patent.

I.INFRINGEMENT

ViiV asserts that Lupin’s generic product would infringe claims 4, 26, 27, 29, 30, 34, 36, 38, 39, and 47 of the '191 Patent. Claim 47 is a formulation claim, while the remaining claims recite methods of treatment. All claims encompass abacavir and 3TC, while certain claims add AZT as the third drug in the combination. There is no dispute that Lupin’s ANDA product will contain AZT and 3TC. The infringement dispute hinges on the abacavir limitation, and whether Lupin’s ANDA product’s use of abacavir sulfate puts the product outside the scope of the asserted claims. Lu-pin argues that it does not infringe any of the claims because (1) the asserted claims do not encompass the sulfate form of aba-cavir; (2) the method claims are only directed to treating the “opportunistic conditions” associated with HIV rather than the HIV infection itself; and (3) there is no evidence that Lupin would induce and contribute to the infringement of the method claims. ViiV disagrees, arguing that (1) abacavir is contained by the abacavir sulfate in Lupin’s generic product; (2) the method claims are aimed at the treatment of the underlying HIV infection; and (3) Lupin clearly intends to infringe the method claims by inducing and contributing to use by clinicians and patients of the claimed combinations.

(A) FINDINGS OF FACT

1. Independent claim 45 recites the chemical compounds of AZT, 3TC, and pure abacavir, also referred to as abacavir free base. '191 Patent, claim 45.

2. Claim 46 depends from claim 45, reciting the formulation of claim 45 in a unit dosage form. '191 Patent, claim 46.

3. Claim 47 depends from claim 46, reciting the formulation of claim 46 in the form of a tablet capsule. '191 Patent, claim 47.

4. Claim 47 is asserted against Lupin.

5. Lupin’s proposed AND A product contains abacavir sulfate, also referred to as the salt form of abaca-vir, 3TC, and AZT. (See, e.g., PTX 135 at 1; PTX 136 at 15; PTX 137 at 44).

6. Abacavir sulfate is formed via a chemical reaction between abacavir free base and sulfuric acid. (Tr. at 215-17, 228, Dr. Langer).

7. Abacavir sulfate has different molecular bonds and a different molecular weight from free base abacavir. (Tr. at 215-17, 228, Dr. Langer).

8. Abacavir sulfate is a distinct chemical compound from free base abaca-vir. (Tr. at 254-56, Dr. Arnold).

9. The '191 Patent does not define claim 47 to encompass abacavir sulfate, and thus Lupin’s generic product does not literally infringe claim 47.

10. There is no evidence that abacavir sulfate and free base abacavir are functional equivalents, as abacavir sulfate has superior stability and handling properties. (Tr. at 220, Dr. Langer; Tr. at 254-55, Dr. Arnold).

11. Claims 4, 26, 27, 29, 30, 34, 36, 38, and 39 of the '191 Patent encompass treatment of the underlying HIV infection rather than merely treatment of the opportunistic infections associated with AIDS. '191 Col. 1:09-20.

12. Claim 4 does not encompass any “physiologically functional derivative” of abacavir, and thus Lupin’s generic product does not literally infringe that claim. See '191 Patent, claim 1-4.

13. Claims 26, 27, 29, 30, 34, 36, 38, and 39 do not encompass the salt form of abacavir, and thus Lupin’s generic product does not literally infringe those claims. See '191 Patent, claims 26, 27, 29, 30, 34, 36, 38, and 39.

14. Lupin’s generic product does not infringe claims 4, 26, 27, 29, 30, 34, 36, 38, and 39 under the doctrine of equivalents.

(B) LEGAL DISCUSSION AND CONCLUSIONS OF LAW

(i) Literal infringement of claim I7

ViiV first argues that Lupin’s generic product will directly infringe claim 47 of the'191 Patent, which is a formulation claim. ViiV has the burden to prove infringement by a preponderance of the evidence. Golden Blount, Inc. v. Robert H. Peterson Co., 438 F.3d 1354, 1363 (Fed.Cir.2006). Claim 47 depends from claim 46, which depends from claim 45. Those three claims follow:

45. A pharmaceutical formulation comprising (IS, 4R)-cis-4-[2-amino-6-(cy-clopropylamino)-9H-purin-9-yl]-2-cy-clopentene-l-methanol, zidovudine, and (2R, cis)-4-amino-l-(2-hydroxymethyl-l,3-oxathiolan-5-yl)-(lH)-pyrimidin-2-one in a ratio of 1 to 20:1 to 20:1 to 10 by weight, in association with one or more pharmaceutically acceptable carriers therefor.

46. A formulation according to claim 45 in a unit dosage form.

47. A formulation according to claim 46 in the form of a tablet capsule.

ViiV asserts that independent claim 45 recites abacavir, AZT, and 3TC, and Lupin’s generic tablet capsule product will infringe dependent claim 47, which claims a tablet capsule unit dosage form. In support, ViiV points to Lupin’s ANDA, which states that Lupin’s generic drug product will contain abacavir, AZT, and 3TC as the active ingredients. In response, Lupin argues that claim 47 is limited to the chemical formulation of “abacavir free base,” i.e., pure abacavir. Lupin argues that its generic product does not contain “abacavir free base,” but rather uses “abacavir sulfate,” or a salt form of abacavir. According to Lupin, the salt form of abacavir has a chemical structure that differs from pure abacavir, and the salt form’s chemical structure is not encompassed by claim 47. ViiV replies that this is a distinction without a difference, as abacavir sulfate invariably contains abacavir.

ViiV is correct when it says that Lupin’s ANDA, in certain places, explicitly states that abacavir, AZT, and 3TC are the ingredients of the generic product. {See, e.g., PTX 152 at LUPIN(TRIZ) 012340; id. at 012373). Lupin’s 30(b)(6) witnesses also stated as much: “Our product is abacavir, lamivudine and zidovudine tablets.” (Tr. at 150-151, Mr. Dahibate). Dr. Langer, ViiV’s expert on infringement, further testified that “abacavir is in abacavir sulfate ... Lupin’s ANDA says that.” (Tr. at 189). Lupin’s ANDA further states that “each film-coated tablet contains the active ingredients 300 mg of abacavir as abacavir sulfate.” (PTX 154 at LUPIN(TRIZ) 000102). Dr. Arnold, Lupin’s expert, acknowledged that Lupin’s product “eventually provides abacavir. That is the active ingredient. Otherwise, the product wouldn’t work.” (Tr. 280).

These statements in isolation would suggest that Lupin’s proposed generic drug contains the identical chemical compound recited in independent claim 45 and is thus encompassed by asserted dependent claim 47. The sum total of the evidence, however, shows otherwise. Lupin’s ANDA product will use abacavir in a salt form, i.e., abacavir sulfate, not abacavir in its free base or pure form. Each ANDA section proffered by ViiV identifies the active ingredient as “abacavir sulfate.” (See, e.g., PTX 135 at 1; PTX 136 at 15; PTX 137 at 44). The proposed ANDA labeling expressly defines the active ingredient as the sulfate or salt form. (PTX 152 at 12355). Although ViiV argues that abacavir is “in” abacavir sulfate, the sulfate form comes into being only after a reaction between abacavir free base and sulfuric acid in isopropyl alcohol, and the resulting salt product has a changed molecular weight and forms new molecular bonds. (Tr. at 215-17, 228, Dr. Langer). As the salt form is only produced after a chemical reaction, it is chemically distinct from aba-cavir free base or pure abacavir. (Tr. at 254-56, Dr. Arnold). It thus does not contain abacavir free base as recited in claim 45. As to the 30(b)(6) testimony, Mr. Dahibate also testified to the cover letter for the ANDA, which recites abaca-vir sulfate, lamivudine, and zidovudine tablets. (Tr. at 152-53). There is no question that Lupin’s proposed tablet must use the sulfate form of abacavir, and not aba-cavir free base, if it is to be consistent with the ANDA submitted to the FDA. (See PTX 152 at 5) (generic drug contains “300 mg of abacavir as abacavir sulfate”). A 30(b)(6) witness’s testimony does not alter the directions provided in the ANDA document, and any generic product must be' consistent with the content of the relevant ANDA.

ViiV argues that Lupin’s planned use of abacavir sulfate in combination with AZT and 3TC nevertheless infringes claim 47, as the tablet capsule eventually provides abacavir when it is administered to a patient. ViiV relies on Merck & Co., Inc. v. Teva Pharmaceuticals USA, Inc., 347 F.3d 1367, 1371 (Fed.Cir.2003) to argue that even if the sulfate form is chemically distinct from abacavir free-base, claim 45 would be understood by a person skilled in the art as encompassing the salt form. In Merck & Co., the Federal Circuit upheld the district court’s finding that the salt form of an acid drug compound infringed the sole claim of the patent, which was a method claim, even though that claim recited only the acid form and not the salt form. Id. at 1372. The Federal Circuit stated the following:

The evidence of all the qualified witnesses was that persons in this field would understand that the acid is the active agent and that the acid is administered when it is in the form of the salt. There was no evidence that the claimed method of treatment is not achieved by the acid salt. The record shows that Teva and Zenith, as well as Merck, label their products with the “free acid equivalent.”

Id. at 1371. The chemical distinction between an acid and a salt was thus discounted, as pharmacologists skilled in the art would have understood the claimed method of treatment to encompass the salt. Id. at 1371-72. ViiV argues that similarly, the Court should conclude that the sulfate of abacavir falls within the scope of abacavir in the free base form. In support, ViiV points to the specification’s statement that “therapeutic use” included “salts of [abaca-vir],” and that “all salts, whether or not derived from a physically acceptable acid or base, are within the scope of the present invention.” '191 Col. 3:25-27. ViiV also directs attention to dependent claim 35, which states the following: “a method according to claim 32, wherein the [abaca-vir] is the succinate salt,” suggesting that the abacavir chemical is intended to include the salt form.

Lupin argues that Merck & Co. is not on point. First, Lupin notes that the claim at issue in that case recited methods of treatment, whereas claim 47 is a chemical formulation claim. Lupin argues that because it was a method claim- in Merck & Co., rather than a formulation claim, the district court was able to apply a special lexicography to define the acid compound as including salts, as the district court relied on the “biology” section of that patent’s specification that was more relevant to the method of treatment, while ignoring the “chemical” section. Merck & Co. v. Teva Pharms. USA, Inc., 228 F.Supp.2d 480, 489 (D.Del.2002). Lupin argues that the district court noted that this was only proper because a method claim was at issue, and the district court would not have done so if the claim “were still a composition claim,” since, in that context, the chemistry section “would be highly instructive.” Id. The Federal Circuit’s affirmation of the district court’s opinion was similarly dependent on the claim’s form as a method claim. See Merck & Co., 347 F.3d at 1372. Further, Lupin argues that construing the only claim of the patent at issue in Merck & Co. as excluding the salt form would have rendered salt form - embodiments described in the specification completely excluded from the patent. Here, in contrast, there are unasserted claims specifically directed at “physiological functional derivatives,” meaning that the salt embodiments described in the '191 Patent would not be excluded by Lupin’s construction, and also suggesting that when the inventors intended to claim derivatives, they did so explicitly, and thus the derivatives should not be read as em compassed by the method claims.

The Court agrees with Lupin that the present facts are distinguishable from Merck & Co. Merck & Co. dealt with a method claim that recited a “method of treatment” that “consists of administering to a patient in need thereof an effective amount of [the drug compound].” Id. at 1370. The Federal Circuit relied on the fact that “[t]he evidence of all the qualified witnesses was that persons in this field would understand that the acid is the active agent and that the acid is administered when it is in the form of the salt.” Id. at 1371. The claim in that case encompassed therapeutic treatments, and there were multiple statements in the specification suggesting that the method of treatment included the salt form. Claim 47 is not a method claim reciting the administration of a drug to a patient for a certain therapy. It is solely a formulation claim, unconcerned with the ultimate effects of the drug compound in the body. Further, there are unasserted claims of the '191 Patent explicitly reciting “physiological functional derivatives” of the drugs, which would include the salt form. Thus, the patentee differentiated between the pure (or free base) form of abacavir and the salt form in the claims themselves, undermining the argument that the salt form is intrinsically encompassed by the free base or pure form. The Court’s ruling does not exclude salt forms altogether from the scope of the patent, as there are unassert-ed claims that encompass derivatives. If salts and derivatives of abacavir were intended to be encompassed by the chemical compound as recited, then there would have been no need for the patentee to claim derivatives and salts of abacavir separately.

As to ViiV’s claim differentiation argument, ViiV correctly states that claim 35 narrows the “lS-methanol” [abacavir] element of claim 32 to “the succinate salt.” As Lupin notes, however, the inventors were inconsistent in their use of dependent claims. Claim 32 claims in part “lS-Methanol” [abacavir]. It does not claim a physiologically functional derivative thereof. Claim 35 depends from claim 32, and narrows the claim to where the “lS-Methanol” [abacavir] is the “succinate salt,” implying that the “succinate salt” is claimed by “lS-methanol” [abacavir]. Claim 48 recites the “lS-methanol” [abacavir] element with “or a physiologically functional derivative thereof.” Then, dependent claim 49 narrows claim 48 to where the “physiologically functional derivative of ‘lS-Methanol’ [Abacavir]” is the “succinate salt.” In one case, the succinate salt is a limitation on “lS-methanol” [abacavir] and the other time it is a limitation on the derivative of “lS-methanol” [abacavir]. The patentee excludes the “lS-methanol” limitation, instead only reciting the “derivative” limitation narrowed to the “succinate salt.” The “succinate salt” claims are inconsistent. The patentee cannot benefit from inconsistent claims drafting.

For these reasons, the Lupin generic ANDA product does not literally infringe claim 47 of the '191 Patent.

(ii) Infringement of claim 17 under doctrine of equivalents

ViiV next argues that Lupin’s generic ANDA product infringes under the doctrine of equivalents. The primary inquiry in applying the doctrine of equivalents is whether “the differences between the claimed invention and the accused device are ... ‘insubstantial.’ ” nCUBE Corp. v. SeaChange Int’l, Inc., 313 F.Supp.2d 361, 376 (D.Del.2004), aff'd, 436 F.3d 1317 (Fed.Cir.2006). A salt form of a drug has properties distinct from the pure or free base form, as the entire purpose behind using the salt form is the form’s superior stability and handling properties. (Tr. at 220, Dr. Langer; Tr. at 254-55, Dr. Arnold). This suggests that the salt and the free base forms are not equivalent, and no evidence was provided otherwise. Further, as discussed, there are unasserted claims that explicitly recite “physiologically functional derivatives” of abacavir. ViiV chose not to assert those claims against Lupin, instead asserting a claim that does not contain that limitation. It would be improper to recapture scope that is absent in the asserted claim, yet present in unas-serted claims, under the doctrine of equivalents. See Abbott Laboratories v. Sandoz, Inc., 566 F.3d 1282, 1297 (Fed.Cir.2009).

(in) Literal infringement of method claims k, 26, 27, 29, 30, 3k, 36, 38, and 39

ViiV also asserts method claims 4, 26, 27, 29, 30, 34, 36, 38, and 39 of the '191 Patent, all reciting methods “for the treatment or prevention of the symptoms or effects of an HIV infection in an infected animal which comprises treating said animal with a therapeutically effective amount” of a combination of abacavir, 3TC, and optionally AZT. ViiV asserts theories of indirect infringement, arguing that Lu-pin’s ANDA shows it would induce and/or contribute to acts of direct infringement of the method claims by doctors and patients.

To induce infringement, the defendant must intend to cause the acts that constitute the direct infringement, DSU Medical Corp. v. JMS Co., 471 F.3d 1293, 1305 (Fed.Cir.2006), and must know that the induced acts constitute infringement. Global-Tech Appliances, Inc. v. SEB S.A.( — U.S.-, 131 S.Ct. 2060, 2068-71, 179 L.Ed.2d 1167 (2011). To be held liable for contributory infringemeht, ViiV must show that Lupin ■ will sell its generic product knowing that it will be used' in an infringing manner. Netgear, Inc. v. Ruckus Wireless, Inc., 852 F.Supp.2d 470, 476 (D.Del.2012). Claims 34, 35, 38, and 39 are nearly identical to claims 26, 27, 29, and 30, except that claims 26, 27, 29, and 30 recite methods of treatment using a combination “comprising” ABC and 3TC, thus permitting (but not requiring) AZT. Those claims are recited below:

All of the asserted method claims (or the independent claims from which they derive) recite the following limitation: “the treatment or prevention of the symptoms or effects of an HIV infection.” The parties dispute whether treatment or prevention of the HIV infection itself falls within the scope of “symptoms or effects.” Lupin argues that the plain meaning of “symptoms or effects” of HIV is limited to opportunistic infections or conditions and not to the HIV infection itself. Because its generic drug product is intended to treat HIV infection, not the symptoms or effects of an infection, Lupin argues it does not indirectly infringe the claims. ViiV disagrees, arguing that Lupin’s generic product is aimed at halting replication of HIV, which is an effect of infection, and it therefore infringes that limitation. The Court construed the “symptoms or effects” term according to its plain and ordinary meaning, but did not specify what this plain and ordinary meaning was, or whether that meaning excluded treatment of the HIV infection itself. (D.1.126 at 2, 3).

Lupin argues that construing “symptoms or effects” to include the HIV infection itself would simply remove the term from the claim in the following manner:

32. A method for the treatment or prevention of the symptoms or effects of an HIV infection in an infected animal....

The Court does not agree. The '191 Patent is aimed at treatments designed to halt viral replication. (Tr. at 81-82, Dr. Blick). The first paragraph of substance in the specification states, “The present invention relates to therapeutic combinations of [the drug compounds] which have anti-HIV activity. The present invention is also concerned with pharmaceutical compositions containing said combinations and their use in the treatment of HIV infections including infections with HIV mutants bearing resistance to nucleoside and/or non-nucleoside inhibitors.” '191 Col. 1:09-20. The specification makes clear that the combinations are designed to treat an HIV infection by inhibiting replication of the HIV virus. There is nothing wrong with construing the “symptoms or effects” claim language to encompass such treatment, especially when those terms are read in light of the specification. “Symptoms” and “effects” are not equivalent. While “symptoms” might be understood to have the restrictive scope argued by Lu-pin, “effects” is a broader term. One “effect” of an HIV infection is the nonstop viral replication resulting in a spread of infection throughout the cells of the body. There is no dispute that Lupin’s ANDA product is intended to halt such progression of the disease. (See PTX 152 at LU-PIN(TRIZ) 12337). It is thus a method for the treatment of the effects of an HIV infection.

The claim language also concerns the “prevention” of symptoms of an HIV infection. One way to prevent the opportunistic conditions (which Lupin argues is what is meant by “symptoms or effects of an HIV infection”) associated with AIDS is to treat the underlying infection. Finally, although it is true that “[a] claim construction that gives meaning to all terms of the claim is preferred over one that does not do so,” Merck & Co. v. Teva Pharms. USA, Inc., 395 F.3d 1364, 1372 (Fed.Cir.2005), that is a mere preference. It would be better to allow for some redundancy than to adopt a construction that is inconsistent with the invention. Thus, Lupin’s generic ANDA product meets the “method for the treatment or prevention of the symptoms or effects of an HIV infection” limitation.

The Court will next consider claim 4 separately from the other method claims. Claim 4 depends from claim 2, which depends from claim 1. Those three claims follow:

1. A method for the treatment or prevention of the symptoms or effects of an HIV infection in an infected animal which comprises treating said animal with a therapeutically effective amount of a combination comprising [abacavir] or a physiologically functional derivative thereof, [AZT] or a physiologically functional derivative thereof, and [3TC] or a physiologically functional derivative thereof.

2. A method according to claim 1 wherein [abacavir] or a physiologically functional derivative thereof, [AZT] or a physiologically function derivative thereof, and [3TC] or a physiologically functional derivative thereof are present in a ratio of 1 to 20:1 to 20:1 to 10 by weight. 4. A method according to claim 2 wherein [abacavir], [AZT] and [3TC] are present in a ratio of 1 to 3:1 to 3:1 to 2 by weight.

The parties dispute whether the “physiologically functional derivative thereof’ limitation of claims 1 and 2 is encompassed or excluded by asserted claim 4. ViiV argues that dependent claim 4 encompasses that limitation, and thus that Lupin’s generic product infringes the claim. Lu-pin disagrees, arguing that claim 4 has been narrowed to exclude the “physiologically functional derivative” limitation. Dependent claim 2 contains “physiologically functional derivative thereof limitations” for all drug compounds, but asserted dependent claim 4 does not. This would suggest that claim 4 does not encompass derivatives. Claim 13, which is also dependent from claim 1, and like claim 4, adds additional weight ratio limitations, follows:

13. A method according to claim 1 wherein [abacavir] or a physiologically functional derivative thereof, [AZT] or a physiologically functional derivative thereof, and [3TC] or a physiologically functional derivative thereof are present in a ratio of 1 to 10:1 to 10:1 to 5 by weight.

Claim 13 explicitly recites the derivative limitation, while asserted claim 4 does not. It would follow that claim 4 does not encompass the derivative limitation. The only conclusion that can be drawn from comparing asserted claim 4 with claims 2 and 13 is that claim 4 has been narrowed to exclude salt derivatives of abacavir, which would exclude Lupin’s accused generic product. Lupin’s generic product does not literally infringe claim 4.

As to the bulk of the method claims, ViiV argues that the reasons for finding noninfringement of formulation claim 47 do not extend to finding non-infringement of method claims 26, 27, 29, 30, 34, 36, 38, and 39. ViiV argues that the method claims are concerned with treatment, and the generic product ultimately treats the patient with abacavir. This gives rise to another discussion of Merck & Co., 347 F.3d at 1367. On the surface, it would appear that because the asserted claims at issue are method claims, the situation becomes analogous to Merck & Co. This does make Merck & Co. a closer fit than it was with formulation claim 47. There are, however, still key differences between the singular method claim of Merck & Co. and the asserted method claims of the '191 Patent. In Merck & Co., there was only a single asserted claim and the specification suggested that the salt form was understood as falling within the scope of that claim. Id. at 1371-72. Here, by contrast, there are unasserted claims that manifestly recite derivatives of abacavir that would include the salt forms. It would not seem true to the patentee’s intentions of claim drafting for the Court to redefine and broaden the asserted claims as implicitly encompassing scope, where the patentee felt it necessary to explicitly claim that scope elsewhere. This is the most important distinction with Merck & Co., as in that case, there was only a single method claim at issue, and construing that claim to include the salt form would not vitiate limitations in unasserted claims. Further, in Merck & Co., there was evidence that the lexicography of the patent defined the acid form of the drug as encompassing the salt form. Id. at 1372. Here, there is no suggestion in the patent that the chemical formula for pure or free base abacavir was specially defined to include the salt form. The inventors’ explicit recitation of separate “physiologically functional derivative thereof’ limitations in unasserted claims suggests they understood them to be different. Finally, Dr. Arnold persuasively explained how the salt form is chemically distinct from the pure or free base form of abacavir, and that the salt form offers superior functionality, and thus the Court cannot find that persons skilled in the art would have understood the pure or free base form of abacavir to be the same thing as, or to encompass, the salt form. (Tr. at 254-57). For these reasons, the instant case is distinguishable from Merck & Co., and Lupin’s generic product does not literally infringe the asserted method claims of the '191 Patent.

(iv) Infringement of method claims 4 26, 27, 29, 30, 31, 36, 38, and 39 under the doctrine of equivalents

For similar reasons as to why the generic product does not infringe the formulation claim under the doctrine of equivalents, Lupin’s generic product does not infringe the method claims under the doctrine of equivalents. Where the patentee explicitly claims certain subject matter in unasserted claims, that subject matter should not be transported into the asserted claims via the doctrine of equivalents. This, however, is what ViiV seeks here, as many unasserted claims contain the “physiologically functional derivative thereof’ limitations, which would encompass the salt form of abaeavir, yet the asserted claims do not. For this reason, Lupin’s generic product does not infringe the method claims of the '191 Patent under the doctrine of equivalents.

II. OBVIOUSNESS

To determine obviousness, the Court must decide whether the subject matter of the claimed invention would have been obvious at the time the invention was made to a person of ordinary skill in the art to which the subject matter of the invention pertains. 35 U.S.C. § 103(a). “Obviousness is a question of law with several underlying factual inquiries: (1) the scope and content of the prior art; (2) the differences between the prior art and the claims at issue; (3) the level of ordinary skill in the field of the invention; and (4) objective considerations such as commercial success, long felt but unsolved need, and the failure of others.” Trans-ocean Offshore Deepwater Drilling, Inc. v. Maersk Drilling USA, Inc., 699 F.3d 1340, 1347 (Fed.Cir.2012). Defendants have the burden of proving the obviousness of the claims by clear and convincing evidence. Id.

Defendants argue that the claimed combinations, abaeavir and 3TC, and abaeavir, 3TC, and AZT, were obvious in light of the prior art. Where a skilled artisan merely pursues known options from a finite number of identified, predictable solutions, the resulting invention is obvious under § 103. In re Cyclobenzap-rine Hydrochloride Extended-Release Capsule Patent Litig., 676 F.3d 1063, 1070 (Fed.Cir.2012). “Where, however, a defendant urges an obviousness finding by ‘merely throwing] metaphorical darts at a board’ in hopes of arriving at a successful result, but ‘the prior art gave either no indication of which parameters were critical or no direction as to which of many possible choices is likely to be successful,’ courts should reject ‘hindsight claims of obviousness.’ ” Id. at 1070-71.

Teva asserts that the combination of abaeavir and 3TC was obvious both because (i) a person skilled in the art (“POSA”) would have been motivated to combine complementary and potent NRTIs to hit HIV early and hard, with a reasonable expectation that such a combination would suppress HIV reproduction and delay or prevent the development of resistant strains of the virus, and (ii) a POSA would have been particularly motivated to replace AZT in the AZT/3TC combination with abaeavir, as abaeavir was an NRTI, yet it avoided the toxicity problems associated with AZT while still complementing 3TC. Lupin argues that a POSA would have been motivated to build upon the success of AZT/3TC by adding a third potent and low toxicity drug to the therapeutic regimen. ViiV disagrees, arguing that combination therapy was unpredictable, the sizeable universe of potentially useful drugs was inconsistent with an obviousness finding, problems of cross-resistance overrode considerations of potency and would have discouraged a POSA from combining abaeavir and 3TC, and it made no sense to alter AZT/3TC by substituting abacavir for AZT, as AZT/3TC was the only known combination that worked.

(A) FINDINGS OF FACT

(i) Level of ordinary skill in the art.

The parties agreed that their definitions of a person skilled in the art are essentially the same. (Tr. at 1583). A person skilled in the art would have a medical degree or a PhD in virology or a related field in the biological sciences with experience in retroviral therapies. (Tr. at 79, Dr. Langer; Tr. at 309, Dr. Zingman).

(ii) Scope and content of the prior art.

(a) Background

The application leading to the '191 Patent was filed on March 28, 1996, and claims priority from two Great Britain applications filed on March 30, 1995, and claims inventions conceived in mid-1994. (JX 1, p.30). Human Immunodeficiency Virus (“HIV”) was first reported in 1983, and was discovered to be the cause of Acquired Immune Deficiency Syndrome (“AIDS”) in 1994. (Tr. at 1219-21, Dr. Ho). As a virus, HIV does its damage through replication. HIV (1) fuses and enters a cell; (2) converts viral RNA to DNA by reverse transcription; (3) integrates the new DNA into the host cell’s nucleus; (4) uses the new DNA to create copies of viral RNA and enzymes; (5) packages the new RNA and enzymes into virions; (6) buds from the cell; (7) cleaving, or cutting, the enzymes into their final form. (Tr. at 987-88, Dr. Larder; Tr. at 1278-79, Dr. Ho). AIDS, which is the final stage of HIV infection, is diagnosed where immune cells (CD4 T cells) fall below a certain level, and the patient is vulnerable to deadly opportunistic infections. (Tr. at 84, Dr. Blick). The AIDS epidemic was a public health crisis in the 1980s and 1990s, having left approximately 300,000 Americans dead. (PTX258).

In 1995, the state of the art in HIV treatment was one of both failure and advancement, with drug researchers and doctors eager to identify effective therapies to halt the progression of the disease. (Tr. at 313-15, Dr. Zingman; Tr. at 1218-21, Dr. Ho). Nucleoside reverse transcriptase inhibitors (“NRTIs”) were the first type of drugs developed for the treatment of HIV. (Tr. at 317, Dr. Zingman; Tr. at 1233-34, Dr. Ho). In order to incorporate itself into the nucleus of a host cell and induce replication, HIV must build a complete DNA chain from its RNA after entering the host cell. (Tr. at 1234-35, Dr. Ho). This is known as the reverse transcription process, and is mediated by an enzyme called reverse transcriptase. (Tr. at 317, Dr. Zingman; Tr. at 1234, Dr. Ho). The DNA chain is made from four protein building blocks, which are known as deoxy-cytidine, deoxyguanine, deoxythymidine, and deoxyadenosine. (Tr. at 476, Dr. Parniak). They are generally referred to as the C, G, T, and A building blocks or bases. (Tr. at 476, Dr. Parniak). NRTIs function as analogs of these building blocks. (Tr. at 477, Dr. Parniak). An NRTI will trick the reverse transcriptase enzyme into incorporating the drug into a growing viral chain. (Tr. at 1234, Dr. Ho). The NRTI then prevents further blocks from being attached to the chain, thus acting as a “chain terminator” and halting replication. (Tr. at 482, Dr. Parniak).

AZT, the first FDA-approved anti-HIV drug, is an NRTI analog to the “T” DNA building block. (Tr. at 136, Dr. Blick; Tr. at 1220, Dr. Ho). AZT was known to be effective at decreasing mortality as a mo-notherapy, but for only a relatively short period of time. (Tr. at 327, Dr. Zingman). AZT also had the drawback of producing severe side effects due to its toxicity, causing patient compliance difficulties. (Tr. at 328, Dr. Zingman). Toxicity occurred because NRTIs may disrupt normal human DNA processes in a similar manner as to how they disrupt viral DNA. (Tr. at 328, Dr. Zingman). Other NRTIs were developed and used in treatment, but no drug provided sustained effectiveness when prescribed as monotherapy. (TTX 153; Tr. at 313-15, Dr. Zingman; Tr. at 1218-21, 1236-37, Dr. Ho). HIV replicates itself at a rapid pace, creating over one billion copies daily. (Tr. at 320, Dr. Zingman). The replication process is error-prone, allowing for millions of mutated variants created daily in an infected person. (PTX 353 at 126). HIV’s ability to mutate rapidly causes the virus to become resistant to monotherapy in a matter of months. (Tr. at 982-83, 993, Dr. Larder; Tr. at 1237, Dr. Ho; Tr. at 445-46, Dr. Zingman; Tr. at 816, Dr. Arnold). Persons skilled in the art sought to solve the problem of treatment failure due to resistance. (Tr. at 991-93, 995-97, 1023-24, Dr. Larder; Tr. at 816, Dr. Arnold).

(b) Was combination therapy established as a treatment strategy as of March 1995?

The '191 Patent sought to solve the problem of viral resistance to monoth-erapy via NRTI combination therapy. '191 Col. 1:16-21. The claims of the patent recite two-drug and three-drug combinations, those combinations being abacavir and 3TC, and abacavir, 3TC, and AZT. See '191 Patent, claims 1-51. The effective filing date is March 30, 1995. The degree to which combination therapy was accepted in the field of anti-HIV drug treatment as of March 1995 is relevant to the obviousness of the '191 Patent. Novo Nordisk A/S v. Caraco Pharm. Laboratories, Ltd., 719 F.3d 1346, 1351 (Fed.Cir.2013). Defendants argue that by March 1995, combination therapy had clearly begun to demonstrate its superiority to monotherapy. ViiV disagrees, arguing that there was still pervasive uncertainty in the field, and combination therapy was far from established.

The Court generally agrees with Defendants that combination therapy was emerging as superior to monotherapy in the field of HIV treatment, with the caveat that the field was still in the midst of considerable uncertainty. As early as June 1993, over a year and a half before the effective filing date, the Journal of Commerce reported on the Ninth International Conference on AIDS in Berlin. (TTX 153). The publication stated that “most AIDS cases now are treated with a combination of drugs because researchers believe this might be a better technique.” (Id.). The failures of monotherapy were recognized: “The most critical point ... is that no currently available monotherapy (use of one drug) will provide as long-lasting benefit as we would all desire.” (Id.). The Hammer article from Journal of Acquired Immune Deficiency Syndromes reported that a “majority of panelists,” ie., clinicians, would “recommend initial combination antiretroviral therapy” for a variety of patient types. The Caliendo reference from AIDS Commentary also described the failure of AZT monotherapy (referring to its benefits as “transient”) and the suspected superiority of combination therapy. (LTX 1490 at 516). The FDA had approved the ddC and AZT combination, and doctors independently prescribed AZT plus ddl. (LTX 1318; TTX 17; Tr. at 315; Tr. at 1361-62, Dr. Ho).

All of these references strongly suggest that the field had been moving toward combination therapy prior to the effective filing date of the '191 Patent. This could be derived even without taking into account the results of the 3TC and AZT trials, presented at the 2nd National Conference on Human Retroviruses and Related Infections, held January 29 to February 2, 1995 in Washington D.C. (TTX 71). AIDS Weekly reported these results: “The combination of lamivudine (3TC) and zidovudine (AZT) has the most potent and longest lasting effect of any retroviral strategy yet tested in clinical trials, according to the result of four Phase II trials conducted in Europe and in North America.” (Id.). This reference explicitly supports the premise that certain types of combination therapy were recognized as the best available treatment.

In arguing that combination therapy was not established, ViiV does cite a trial stating that monotherapy had “the best benefit for patients,” but that trial came before the 3TC/AZT announcement and only touched upon the AZT and ddl combination. (PTX 440 at PB0261). It further is a single study of a single combination, which does not alter the fact that combination therapy was generally being pursued in the field. ViiV also cites the The Medical Letter in opposition, as that reference does state that monotherapy was the recognized preferential treatment, but even that reference suggested the suspected superiority of combinational therapy over monotherapy: “Concurrent use of two or more drugs may prove to be more effective than monotherapy.” (PTX 251 at 87, 88, 90 n.l). Thus, the evidence is clear and convincing that combination therapy was generally thought to offer better treatment opportunities by March 1995.

(c) Universe of potential anti-HIV drugs for combination.

The size of the universe of potential drugs that a person skilled in the art would encounter when seeking an effective combination is relevant to the obviousness analysis. See In re Kubin, 561 F.3d 1351, 1361 (Fed.Cir.2009). The more potentialities, the less likely that a particular combination is obvious. Id. Where options are fewer, indicia of obviousness increases. Id. Defendants argue that a person skilled in the art would look toward a small group of promising NRTIs for potential combinations, as NRTIs were the most effective and best understood class of drugs. ViiV disagrees, arguing that the universe was much larger than Defendants state, and that it certainly included drugs in classes other than NRTIs.

The Court finds that this factor weighs slightly against a finding of obviousness. It is true that good reasons existed to explore the NRTI category for combination research. As of the filing date, all four FDA-approved anti-HIV medications (AZT, ddl, ddC, and d4T) were NRTIs. (Tr. at 317-18, 321-24, Dr. Zingman; Tr. at 486, Dr. Parniak). The AZT and 3TC combination consisted of two NRTIs and was the first HIV therapy to offer lasting clinical benefits. (TTX 17, TTX 71; Tr. at 1381-82, 1391 Dr. Ho). Although evidence suggested that a particular mutational relationship between those two drugs gave rise to the combination’s benefits (see id.) it would follow that persons skilled in the art would attempt to build on the success garnered from combinations in the NRTI class. At least one reference did show a special focus on NRTIs, with one researcher stating, “In the last year, there have been more clinical successes with [NRTIs] than with any other class of compounds.” (TTX 224 at 45). “A powerful platform for drug discovery, in particular [NRTIs], may well set the stage for modifying the predestined pathogenesis of HIV-1.” (Id. at 46).

All of this being said, however, the Court agrees with ViiV that a person of ordinary skill in the art would not completely limit herself to NRTIs in considering drug combinations. ViiV rightly points out that, as of the time of filing, at least 28 drags were in human clinical trials. (TTX 24; PTX 358; PTX 466; TTX 196; PTX 280; PTX 255; PTX 396; PTX 362; PTX 254; PTX 399; PTX 418; PTX 334; PTX 449; PTX 462; PTX 269; Tr. at 1231, Dr. Ho). Of these 28 drugs, thirteen were not NRTIs: eight were protease inhibitors (“Pis”) and five were non-nucleoside reverse transcriptase inhibitors (“NNRTis”). (Tr. at 1231-36). NNRTis were thought to have the potential for less toxicity compared with the other drag classes, making them desirable research targets, especially considering the NRTI toxicity issue. (Tr. at 606, Dr. Parniak; PTX 491 at 103-04). Pis were identified as a “potent new class of drugs[.]” (PTX 251 at 88). Defendants argue, and Dr. Parniak testified, that problems with bioa-vailability and manufacturing would have discouraged research with Pis, but it was reported that, despite these difficulties, “there [was] still merit in pursuing the protease inhibitors[.]” (TTX 224 at 46). Dr. Parniak admitted that Pis were available for experimentation, and that he would consider combining NNRTis and Pis. (Tr. at 604, 428). Defendants’ other experts made similar admissions. (Tr. at 428-29, Dr. Zingman; Tr. at 821-22, Dr. Arnold). Thus, the experts essentially agree that a person skilled in the art would not limit herself to NRTIs. As Lupin stated in its brief, “[scientists were eager for new drugs.” (D.I.202, p. 7). It makes sense for drug developers to pursue combinations in both the known and the less known classes, especially in what were still perilously uncertain days for HIV patients. Further, a patent application of one of ViiVs experts, Dr. Larder, specifically teaches that NRTIs could be combined with NNRTis and Pis. (See TTX 204). Pis and NNRTis were on the table for combination therapy.

(d) Predictability of combination therapy?

The next inquiry into the scope of the prior art is the predictability of combination therapy. ■ Defendants further argue that persons skilled in the art were armed with specific rationales that would lead them to the claimed combinations. Specifically, the AZT and 3TC combination’s success would steer drag researchers to incrementally improve upon that combination to achieve predictable results. Teva argues that the AZT and 3TC combination would lead a person skilled in the art to combine abacavir and 3TC, as abacavir and 3TC would offer similar potency to the AZT/ 3TC combination, but with less toxicity. Lupin argues that the AZT/3TC combination would lead a person skilled in the art to improve the potency of that combination by adding abacavir. ViiV disagrees, arguing that the field was generally unpredictable, AZT and 3TC was the only known effective combination, but that effectiveness was due to a unique mutational interplay between the drugs. ViiV further argues that issues of cross-resistance would discourage combining abacavir and 3TC.

AZT, the first anti-HIV drug sanctioned by the FDA, had been approved for mo-notherapy since 1987. (Tr. at 1220, Dr. Ho). AZT was a potent inhibitor of HIV, but it produced toxic side effects severe enough to cause some patients to refuse it. (Tr. at 327-28, Dr. Zingman; TTX 56 at 736-37; TTX 78; TTX 202). Moreover, despite AZT’s initial potency, the benefits of AZT monotherapy were short-lived. (Id.; Tr. at 1220, Dr. Ho). After a few months, the therapeutic benefit was lost due to the rapid emergence of a drug-resistant virus, resulting in treatment failure and patient death. (Tr. at 1220, 1237, Dr. Ho; PTX 128). Researchers looked to alternatives for AZT in order to skirt the drug’s resistance and toxicity issues. 3TC’s potency was similar to AZT’s, yet it was much less toxic. (Tr. at 335, 345-47, 374, Dr. Zingman; TTX 56; TTX 224). Like AZT, however, 3TC’s initial therapeutic effectiveness as a monotherapy quickly waned. (Tr. at 423-24, Dr. Zingman). 3TC gave rise to resistance and was not effective as a monotherapy. (Tr. at 423, Dr. Zingman; Tr. at 1220, Dr. Ho). Three other NRTIs, ddl, ddC, and d4T, all failed as monotherapies due to the emergence of resistance in the virus. (Tr. at 1220, Dr. Ho).

All parties agree that the AZT and 3TC combination was a momentous development in the field. Results from the corresponding trials were described as a “breath of fresh air,” and the combination was said to offer “the most potent and longest lasting effect of any antiretroviral strategy yet tested in clinical trials.” (TTX 71 at 2; Tr. at 339, Dr. Zingman). AZT and 3TC effectively delayed the emergence of resistant strains of HIV, even though neither drug did so individually. (Id.; TTX 224; TTX 300; Tr. at 337-39). The efficacy of the 3TC and AZT combination was thought to depend upon a mutation in the M184 reverse transcrip-tase gene that made the virus resistant to 3TC, but overrode mutations conferring AZT resistance, thus resensitizing previously AZT-resistant HIV to the antiviral effects of AZT. (TTX 71 at 3).

Defendants argue that good reasons existed to focus on abacavir as a low toxic and potent candidate for combination therapy. ViiV disagrees, arguing that there was no reason to focus on abacavir among the myriad of available compounds. Aba-cavir is an analog of another then experimental anti-HIV drug known as earbovir. Both drugs metabolize to the same antiviral form in the body, earbovir triphosp-hate, albeit via different routes. (TTX 265, Abstract 184; Tr. at 515, 586, Dr. Parniak; Tr. at 1373-74, Dr. Ho). Both are “G” analogs. (Id.). Carbovir was reported to be a potent inhibitor of HIV and to have synergistic in vitro activity with AZT (a “T” analog) and ddC (a “C” analog). (PTX 438 at 967; TTX 93 at 2-3; TTX 228 at 90-92). Carbovir was discussed in the prior art as a potential alternative to AZT. (Tr. at 558-61, 586, Dr. Parniak; TTX 78 at 437). ViiV argues that carbovir’s poor oral bioavailability and reported toxicity in dogs caused drug developers to abandon it, and they likewise would have looked away from carbovir’s analog, abacavir. It is true that carbovir had poor bioavailability, and in one reference, was reported to cause toxicity in dogs. (PTX 438 at 967; Tr. at 515-17, 599, Dr. Parniak; TTX 93; TTX 228). However, this did not apply to abacavir, because abacavir was known to offer sufficient oral bioavailability and to be nontoxic in laboratory animals. (TTX 265 at 16, 186, 188; Tr. at 352-53, Dr. Zingman; Tr. at 1375-76). Dr. Ho testified that carbovir’s toxicity report would be a “red flag” to researchers investigating abacavir, but he also admitted that a researcher would understand that toxicity issues would be resolved were a drug in phase 1 trials. (Tr. at 1294, 1377-78). As of October 1994, abacavir was in Phase I human clinical trials. (TTX 196; TTX 116 at § 8). Carbovir’s toxicity would not have been imputed to abacavir.

ViiV argues that a person skilled in the art had no reason to focus on abacavir in particular. ViiV points out that the first abacavir data was not published until October 1994 at the “ICAAC” conference, and that abacavir was only described in five out of more than a thousand abstracts presented at that conference. (Tr. at 442-43, Dr. Zingman; TTX 265). One publication reciting the major points of the conference, however, specifically highlighted “Wellcome’s 1592UB9,” ie., abacavir. (TTX 196). This suggests that abacavir stood out among the topics covered at the conference. ViiV also argues that abaca-vir’s potency was in doubt, as one study showed that abacavir was 50 to 100 times less potent than AZT. (TTX. 265 at 182). The weight of the scientific literature, however, shows that abacavir was comparably potent to AZT. (TTX 78; TTX 265 at 182; TTX 258 at 2:65-68, Tr. at 511-17, 559-61, 581, Dr. Parniak). Abacavir also had lower toxicity than AZT, was synergistic with other compounds, and penetrated the central nervous system, which is a desirable feature for an anti-HIV medication. (Id.). Abacavir was reported to have in vitro synergistic activity with AZT, ddl, and ddC. (TTX 265 at 16). Abacavir was reported to be “an attractive candidate for clinical evaluation.” (TTX 265 at 16, 188). It was also “an important candidate for further development as an anti-HIV drug for combination therapy,” due to its “cross-resistance profile and the relatively slow emergence of resistance.” (TTX 265 at 182). Thus, the evidence shows that aba-cavir would have been a ripe candidate for researching new combination therapies.

Defendants argue that because the AZT and 3TC combination was the best known combination, and abacavir was known as a particularly strong candidate for future combinations, the claimed combinations bringing those drugs together were obvious. ViiV argues that the fact that all combinations other than AZT and 3TC had failed showed the extreme unpredictability of the field. Defendants point to other allegedly successful combinations to show that it was not an unpredictable field. Defendants rely on the '191 Patent’s specification to show that AZT was known to combine well with other compounds. The specification states, “The combination of [AZT] with either ddC or ddl has shown promising results in HIV infected patients[.]” '191 Col. 1:66-67. ViiV points out that the studies relied on in the specification for this statement were outdated by March 30,1995, and that it was understood that those combinations were in fact not effective. Defendants counter that admissions in the specification regarding the prior art are binding on the patentee.

The Court accepts the statement that AZT plus ddl or ddC were regarded as “promising.” That is not the same thing as saying they were effective. Defendants themselves, however, cite references that contain statements indicating that those combinations were not effective long-term. It would not make sense for the Court to allow Defendants to rely on those references where they support the obviousness case, but to pretend that certain statements unfavorable to the obviousness analysis do not exist. AIDS Weekly from February 1995, a Teva exhibit that Defendants rely on to show the success of AZT and 3TC, also discusses the AZT/ddC Phase II trial. (TTX 71 at 5). That trial showed that therapeutic benefits of AZT/ddC were not sustained at 24 weeks. (Id.). The Hammer reference, which is both a ViiV and Lupin exhibit, is relied on by Defendants to show the general acceptance of combination therapy and to support the theory that potency was understood to lessen the problem of resistance. (LTX 1324; PTX 344; D.I. 205 at 15). That reference also explains that no combination therapy, including AZT/ddC and AZT/ ddl, had been shown “beneficial in delaying clinical disease progression or in improving survival.” (Id. at S28) (italics in original). As to whether Hammer supports Defendants’ position that potency was understood to be the most important factor, Dr. Hammer did state, “Perhaps it is better to hit as hard as you can as early as you can,” and the general consensus was that combination therapy should be started earlier rather than later in treatment. (Id. at S36). There is nothing in Hammer, however, that suggests that combination therapy was predictably effective. It in fact suggests strongly otherwise, as there was not even any proof of “clear-cut clinical benefits” of combination therapy. (Id. at S36). Doctors “could not recommend one combination over another based on current data.” (Id. at S34). Defendants’ own physician expert admitted that he regarded antiretroviral therapy to be “quite confusing” in 1995. (Tr. at 762, Dr. Laurence).

Defendants also rely on results from the “Thompson” study that indicated that AZT plus ddC or ddl afforded greater survival benefit than did starting on AZT and then switching to ddC or ddl. (Id.). According to Defendants, these results, juxtaposed with what was known about AZT/3TC, suggest the obviousness of the claimed combinations. Defendants, however, admit that no definitive conclusions could be drawn from this study, as it was a retrospective (or “lookback”) study rather than a prospective study, and that prospective studies were much better. (Tr. at 747, 48). Later prospective studies showed that AZT and ddl provided no better results than monotherapy, or, in the case of AZT and ddC, produced worse results. (Tr. at 1246, Dr. Ho; PTX 420; PTX 440 at Abstract PB0261; Tr. at 633, Dr. Parn-iak; PTX 268 at PB0266; PTX 344). It was also known that AZT combined with ddC showed signs of increased incidence of serious toxicity in patients in advanced stages of the disease. (PTX 432 at 4253; Tr. at 1246-47, Dr. Ho). Other combinations, including AZT and interferon, and AZT and nevirapine, did not display good results. (PTX 315 at 059B; PTX 344 at 0012152-53).

The AZT and 3TC combination was the only therapy known to provide prolonged viral load reduction and increase in CD4 count as of the priority date. (TTX at 17; TTX at 71; TTX 224). No other combination was recognized as providing sustained therapeutic effects. As one reference stated, that combination was a “breath of fresh air” to the field, ie., it provided something sorely lacking. (TTX at 71). The high degree of failure suggests that combination therapy could not be considered a predictable field.

Defendants argue that the claimed combinations are obvious in part because each of abacavir, 3TC, and AZT is an analog to a different DNA building block (the C, G, and T bases, respectively). These blocks are essential .to the reverse transcription process and thus HIV’s ability to replicate. Because each drug would inhibit replication at different sites of the growing viral DNA chain, they would not compete with one another to effectuate their anti-HIV activity. Defendants argue that the combination of differing analogs was understood to provide synergistic (or at least additive) effects. Defendants argue that persons skilled in the art knew of the beneficial nature of combining NRTIs operating on different sites of the DNA chain, and would thus be motivated to combine the claimed combinations with a reasonable expectation of success. ViiV disagrees, arguing that Defendants provide no evidence that persons skilled in the art were aware of the beneficial nature of the specific drug interactions at play.

In support of this position, Defendants rely on the testimony of their experts. Dr. Zingman testified, “By March of 1995, we already had pretty good evidence that it would be helpful to have complementary nucleoside reverse transcriptase inhibitors, and that would be one way to put them together as a combination.” (Tr. at 326). “[W]e started to get information about potential antagonism between the cytosine analogs, so we started to get information that it wasn’t a good idea to use two T drugs, for example[.]” (Tr. at 334). He testified as to an expectation for success: “[T]he potential to join abacavir and 3TC because one was a G analog and one was a C analog and, that you’d expect they would work well together.” (Tr. at 376). Dr. Zingman continued that “combination therapy targeting different DNA bases was already established as a treatment option for people with HIV infection.” (Tr. at 379). Dr. Parniak echoed Dr. Zing-man’s opinion, testifying in great detail as to how the strands of DNA are made in the reverse transcription process, and how the component drugs work to terminate the DNA chain, and explaining the expected benefit derived from combinations where the analogs do not compete for the same site on the DNA chain. (Tr. at 477, 482-86, 516).

Aside from expert testimony, however, Defendants do not provide a single reference to support the premise that combining analogs of different bases was known to provide a more potent combination. It is true that certain combinations having different bases (at least AZT and 3TC) were reported as offering significant clinical benefits. Defendants, however, do not cite a single reference or publication reporting that the therapeutic benefits of combination therapy could be explained by the drugs affecting different bases of the DNA chain. Nor did Defendants’ experts rely on any references in support. Dr. Zingman testified that “we had pretty good evidence” that combining NRTIs with complementary bases was known to be effective, yet he never actually identified that evidence. Likewise, Dr. Parniak testified that it was known that certain combinations having two NRTIs with different bases provided additive to synergistic inhibition of HIV replication, but he never provided any studies or publications suggesting this was the case. In fact, his deposition testimony was that he could not identify any references that taught to combine compounds with different bases. There is no reference in the record showing that such a sophisticated understanding of combination therapy existed as of March 1995.

Lupin cites Schinazi 1995 for the field’s supposed recognition that NRTIs with the same mechanism of action should not be combined, but that reference in no way refers to the benefits of combining NRTIs with different analog bases. It is instead concerned with the discovery that structurally similar NRTIs may differ significantly in regard to levels of toxicity. Lu-pin also cites AIDS Weekly 1995 for the proposition that researchers realized that if the success of the 3TC and AZT combination was “due to specific interactions, it may lead to rational strategies for combination therapy instead of random choices from a