Citations
- 89 F. Supp. 3d 641
Full opinion text
FINDING OF FACT AND CONCLUSIONS OF LAW
HOCHBERG, District Judge:
This Opinion constitutes the Court’s findings of facts and conclusions of law pursuant to Federal Rule of Civil Procedure 52.
I. INTRODUCTION
Atelvia® — the osteoporosis drug covered by the challenged patents — purports to solve a problem experienced by patients who used earlier osteoporosis drugs: if ■the earlier drugs were taken with a meal, the active ingredient was captured by the calcium found in food molecules and was not absorbed into the body. When the medicine failed to enter the bloodstream, patients’ bones became susceptible to fractures. Atelvia® addressed this “food effect” by combining the active ingredient risedronate with a calcium-blocking agent, EDTA, thus permitting patients to take the drug with a meal and still receive an effective dose.
•It is uncontested that prior art disclosed combinations of the active ingredient and the calcium-blocking agent EDTA to increase absorption. The closest reference — the Brazilian Application — disclosed two mechanisms to increase absorption: (1) a process called chelation, where EDTA binds to calcium molecules in food and blocks them from capturing the active ingredient; and (2) permeability enhancement, where large doses of EDTA spread the pathways between intestinal cells, allowing more active ingredient to pass from the intestine into the bloodstream.
By binding to calcium ions in food, che-lation increases absorption only when a' patient has eaten a meal; absorption of the active ingredient is thus similar regardless of whether a patient has eaten or not. On the other hand, permeability enhancement amplifies overall absorption of any intestinal content. Increased intestinal permeability was viewed as harmful because other drugs or bacteria could also more easily pass into the bloodstream.
Atelvia® employs only the first mechanism: it uses EDTA as a chelator to block the calcium in food, but not to enhance overall intestinal permeability. This achieves what the challenged patents call “pharmaceutically effective absorption,” a limitation defined as similar absorption whether a patient has eaten or fasted. Fed exposure within about 50% of fasting exposure is expected to be “pharmaceuti-cally effective absorption.” Except for the “pharmaceutically effective absorption” limitation, the parties agree that the Brazilian Application contains “all of the elements of the asserted claim[s].” Thus, the main dispute is narrow: in light of the Brazilian Application’s disclosure of EDTA’s two mechanisms of absorption, whether it was obvious to modify the reference — using only the first disclosed mechanism of chelation and excluding the second disclosed mechanism of enhanced permeability — thus permitting a patient to take her osteoporosis medicine and receive a similar dose regardless of whether she has or has not eaten. In other words, was it obvious to use EDTA only as a calcium blocking agent to defeat the food effect, and would a skilled artisan have had a reasonable expectation of success in so doing?
II. JURISDICTION
This Court has subject matter jurisdiction over this case pursuant to the patent laws of the United States and 28 U.S.C. §§ 1331, 1338, 1367,2201 and 2202. Venue is proper in this District under 28 U.S.C. §§ 1391 and 1400(b). This Court has jurisdiction over the parties.
III. BACKGROUND
a. Procedural
Plaintiffs Warner Chilcott Co., LLC, and Warner Chilcott (US), LLC, (collectively “Plaintiffs” or “Warner”) bring this patent infringement action against Teva Pharmaceuticals USA, Inc., (“Teva”) under the Federal Food, Drug, and Cosmetics Act (“FFDCA”), and, more specifically, the Hatch-Waxman Amendments to that law. Plaintiffs assert that two patents protect Atelvia® from generic competition: U.S. Patent No. 7,645,459 (the “'459 patent”) and U.S. Patent No. 7,645,460 (the “'460 patent”). Both patents describe a delayed-release formulation of the active ingredient risedronate in combination with ethylene diamine tetraacetic acid (“EDTA”). Warner acquired these patents when it purchased The Proctor & Gamble Company’s pharmaceutical division in August 2009. (Joint Stipulation of Facts ¶ 3, Dkt. No. 270). Plaintiffs hold an approved New Drug Application (“NDA”), No. 22-560, under § 505(a) of the FFDCA, 21 U.S.C. § 355(a), for a delayed-release risedronate tablet formulation containing 35 mg of risedronate sodium and 100 mg of disodium EDTA, and marketed as Atel-via®. (Joint Stipulation of Facts ¶¶ 5, 70, 71). These tablets were approved by the Federal Food and Drug Administration (“FDA”) on October 8, 2010, and are promoted for the treatment of osteoporosis. (Joint Stipulation of Facts ¶ 69). Warner listed the '459, '460 patents and U.S. Patent No. 8,246,989 in the FDA publication “Approved Drug Products with Therapeutic Equivalence Evaluations” (the “Orange Book”), in connection with Atelvia®. (Joint Stipulation of Facts ¶ 77).
As required by 21 U.S.C. § 355(j)(2)(A)(vii)(IV), Defendant Teva provided Plaintiffs with a “paragraph IV certification,” notifying Plaintiffs that they had submitted an Abbreviated New Drug Application (“ANDA”), No. 20-3217, to FDA seeking approval to manufacture and market generic versions of Atelvia® before the expiration of the '460 and '459 patents. Warner brought this patent infringement action against Teva within the forty-five day statutory period, filing a Complaint against the Defendant. Teva asserted counterclaims, seeking a finding that the challenged patents are invalid. Warner also filed patent infringement actions against the pharmaceutical companies Watson Laboratories, Ranbaxy, and Impax Laboratories, asserting these same patents. The Watson, Ranbaxy, and Im-pax actions were each resolved by settlement.
In its case against Teva, Warner has dropped all asserted claims of U.S. Patent No. 8,246,989, and all asserted claims of the '459 and '460 patents except for claim 16 of the '459 patent and claim 20 of the '460 patent. Teva has stipulated to infringement of these claims. (Joint Stipulation of Facts ¶ 40). A bench trial was held regarding the validity of claim 16 of the '459 patent and claim 20 of the '460 patent.
b. Technology At Issue
The challenged patents claim an active ingredient called risedronate sodium. This drug is a member of a class called bisphosphonates, which have been used for decades to treat osteoporosis. This active ingredient is combined with an inactive ingredient called disodium EDTA, which chelates — or binds — metal ions in food, blocking them from capturing the active ingredient when a patient has eaten.
1. Bisphosphonates
Bisphosphonates have been used since the 1980s to treat osteoporosis and Paget’s disease. (Trial Tr. lA.100:16-25). These diseases are characterized by a weakening of the bone. In a healthy human body, bone tissue is continually regenerated in an equilibrium of bone growth and bone disintegration. (Tr. 1 A.103:14 — 104:9). Os-teoblasts, a type of cell that builds new bone, are balanced by osteoclasts, a type of cell that destroys bone in a process called resorption. (Id.; Joint Stipulation of Facts ¶¶ 84, 85). In patients with osteoporosis, this normal balance is disrupted and bone resorption exceeds bone growth, leading to lower bone mass and a higher chance of fracture. (Tr. lA.104:l-6).
Bisphosphonates have a strong affinity for the calcium crystals in bone, binding tightly to bone surfaces. (Tr. 1A.104:10-17). When a bone-destroying osteoclast engulfs a bone particle that is attached to a molecule of bisphosphonate, the osteo-clast cell becomes less active or is destroyed. (Id.; PTX 135, at 176). Consequently, bisphosphonates inhibit bone resorption. (DTX 167, at 280). Over time, the administration of bisphospho-nates results in less active bone-destroying osteoclasts, less resorption, and more bone tissue. (Tr. ÍA.104:15-24). Many pharmaceutical companies have developed species of bisphosphonate for the treatment of osteoporosis. For instance, Warner marketed a 35 mg delayed-release risedronate tablet, called Actonel®, which is the predecessor drug to the Atelvia® drug at issue. Warner held patents covering risedronate and Warner’s Aotonel® product, which expired on December 10, 2013. Merck developed an alendronate product, marketed as Fosamax®; and Hoffmann-La Roche developed an iban-dronate product, marketed as Boniva®. (Joint Stipulation of Facts ¶¶42, 44, 57).
2. The “Food Effect”
Drugs that are administered by mouth travel from the mouth to the stomach, and then through the pylorus to the lower gastrointestinal tract — which includes the small and large intestine. • (Joint.Stipulation of Facts ¶¶ 88, 89). Bisphosphonate absorption occurs, to the largest extent, in the small intestine. (PTX 135, at 179). The small intestine consists of the duodenum, jejunum, and ileum. (DTX 234, at 589; Tr. lA.106:3-6). There, the bisphos-phonate passes from the intestines into the bloodstream.
There are two routes of transportation for molecules to pass from the intestine into the bloodstream: passing through the intestinal membrane cells themselves or passing through the spaces between the cells, called the tight junctions. (PTX 90, at 1744; Tr. lA.107:l-8). Bisphospho-nates do not pass through the membrane cells. Instead, they travel between the cells, through the tight junctions. (DTX 273, at 231; PTX 135, at 178-79; Tr. 1A.107:9-18). Once in the bloodstream, the bisphosphonate circulates; some is excreted and some is delivered to the bones, the site of the drug’s action.- (DTX 208, at 289; Tr. 1A.107:14-18).
Bisphosphonates are not absorbed, and do not pass into the bloodstream, when taken with a meal. This class of drug not only binds to the calcium in bone, it also binds to any stray calcium ions and other metals it encounters in the stomach and intestines after a meal. (PTX 135, at 178; PTX 90, at 1745; Tr. 1A.108:23-109:4). In the gastrointestinal tract, calcium captures bisphosphonate, forming a combined ealci-um-bisphosphonate complex that is insoluble and is too big to pass through the intestinal tight junctions and into the bloodstream. (DTX 167, at 280, 283). Thus, when an osteoporosis patient simultaneously eats and takes her bisphospho-nate, she does not receive the benefit of the medicine because it never reaches the bone. (Tr. 1A.110:21-111:1). This phenomenon is known as the “food effect.” Because bisphosphonates interact with food, Warner’s predecessor drug Aotonel® had to be taken when the patient had fasted, specifically, after an overnight fast and at least 30 minutes before eating or drinking. (Joint Stipulation of Facts ¶ 53).
3. Chelating Agents
The compound disodium EDTA binds to calcium and other divalent cations. This process is called chelation and EDTA is one of the most widely used and strongest chelators of calcium. (Tr. lA.117:l-8). It tightly sequesters divalent ions, after which the ions cannot interact with other molecules. (Tr. 2A.26:9-27:5).
The bisphosphonate literature had shown that administering EDTA with bis-phosphonate increased bisphosphonate absorption. Two mechanisms account for the increase in absorption: (1) chelation, in that EDTA acted as a calcium blocker; and (2) permeability enhancement, in that EDTA directly increased the permeability of the intestines. (See DTX 167, at 283; PTX 90, at 1745).
The first mechanism, calcium chelation, operates by blocking calcium from capturing the bisphosphonate active ingredient via competitive inhibition. ■ (See DTX 167, at 283; PTX 90, at 1745). The active ingredient and the chelating agent both compete for the same pool of stray calcium. By introducing enough chelating agent, stray calcium is more likely to capture the chelating • agent than the active ingredient. (Tr. 2B.40:l-2). Like a decoy, chelating agents block calcium ions from capturing the bisphosphonate, while the bisphosphonate remains free to enter the bloodstream without interference.
The second mechanism, increasing intestinal permeability, works by widening the pathway between the tight junctions of intestinal cells — by which bisphosphonate travels from the intestine into the bloodstream — permitting more bisphosphonate to be absorbed. (DTX 273, at 232; DTX 167, at 283; PTX 90, at 1745). The tight junctions between cells have molecules of calcium embedded in the channels. EDTA binds to these molecules, making the spaces between cells wider, and increasing permeability for many particles. (DTX 167, at 283). Thus, larger molecules like bisphosphonates pass more easily into the bloodstream. (PTX 90, at 1745; PTX 135, at 179). But spreading the tight junctions creates a risk that bacterial fragments and increased levels of coadministered drugs will pass through these wider pathways to the bloodstream. (PTX 175, at 1249). Consequently, unduly spreading the tight junctions was viewed as undesirable. . (DTX 167, at 280; PTX 90, at 1745; PTX 135, at 185).
c. The Challenged Patents
Both the '459 and '460 patents share a provisional application filed on May 24, 2004. The utility application that issued as the '459 patent was filed on April 15, 2005. The utility application that issued as the '460 patent was filed on November 23, 2005 and is a continuation-in-part of the application that issued as the '459 patent. The '459 patent, entitled “Dosage Forms of Bisphosphonates,” and the '460 patent, entitled “Dosage Forms of Risedronate,” both issued on January 12, 2010. The patentee disclaimed the terminal part of the '460 patent beyond the expiration of the '459 patent, and both are scheduled to expire on January 9, 2028. (Joint Stipulation of Facts ¶¶ 34, 38). The inventors are listed as Richard Dansereau and David Burgio.
Claim 16 of the '459 patent, like claim 20 of the '460 patent, comprises one independent claim and several additional dependent claims. Claim 16 of the '459 patent is reproduced below:
8. An oral dosage form having pharmaceutically effective absorption comprising:
(a) from about 1 mg to about 500 mg of risedronate sodium;
(b) from about 75 mg to about 250 mg of disodium EDTA; and
(c) an enteric coating which provides for release of the risedronate sodium and the disodium EDTA in the lower gastrointestinal tract of a mammal.
13. The oral dosage fomi of claim 8 comprising from about 10 mg to about 50 mg of risedronate sodium.
14. The oral dosage form of claim 13 comprising about 100 mg of the disodium EDTA.
15. The oral dosage form of claim 14 comprising about 35 mg of risedronate sodium.
16. The oral dosage form of claim 15 wherein the enteric coating is a methacrylic acid copolymer.
(DTX 2, '459 patent, col. 38, 11. 50-57, col. 39, 11. 5-13). Claim 20 of the '460 patent is reproduced below:
8. Ah oral dosage form having pharmaceutically effective absorption comprising:
(a) from about 1 mg to about 250 mg risedronate sodium;
(b) from about 25 mg to about 500 mg of disodium EDTA; and
(c) an enteric coating which provides for immediate release of the risedronate sodium and the di sodium EDTA in the small intestine of a mammal.
15. The oral dosage fomi of claim 8 comprising from about 15 mg to about 55 mg of the risedronate sodium.
16. The oral dosage form of claim 15 comprising from about 75 mg to about 250 mg of the disodium EDTA.
17. The oral dosage form of claim 16 comprising about 35 mg of the risedronate sodium.
19. The oral dosage fomi of claim 17 comprising about 100 mg of the disodium EDTA.
20. The oral dosage fomi of claim 19 wherein the enteric coating is a methacrylic acid copolymer.
(DTX 3, '460 patent, col. 24, 11. 47-55, col. 25,11. 8-20).
As shown above, claim 16 of the '459 patent and claim 20 of the '460 patent are both limited to an oral dosage form with 35 mg of risedronate sodium, 100 mg of diso-dium EDTA, and a methacrylic acid copo-lymer enteric coating. Claim 16 of the '459 patent, differs from claim 20 of the '460 patent in the location of release of the formulation: claim 16 requires “release ... in the lower gastrointestinal ■ tract,” whereas claim 20 requires “release ... in the small intestine.” The small intestine is part of the lower gastrointestinal tract. (Joint Stipulation of Fact ¶ 89). Claim 20 of the '460 patent also adds the limitation “immediate release,” which means “dissolution of the core tablet in less than 60 minutes, when measured by standard USP definitions.” (DTX 3, '460 patent, col. 4,11. 13-16).
One feature of the claimed invention is the addition of the limitation in both claims called “pharmaceutically effective absorption,” which is defined in both the '459 and '460 patents as:
an amount of a chelating compound high enough to significantly bind the metal ions and minerals in food but low enough not to significantly alter absorption of the bisphosphonate as compared to absorption in the fasted state. That is, absorption is similar with or without food. Given the high variability of bis-phosphonate absorption, fed exposure within about 50% of fasting exposure is expected to be “pharmaceutically effective absorption.” _
(DTX 2, '459 patent, col. 4, 11. 59-67; DTX 8, '460 patent, col. 4, 11. 64-col. 5, 11. 5).
The patent applications that issued as the '459 and '460 patents originally did not contain the term “pharmaceutically effective absorption.” (PTX 3, at 1138). After the PTO examiner rejected the claims as unpatentable — because earlier references disclosed bisphosphonates combined with EDTA to increase absorption — the paten-tee amended every claim to add the limitation “pharmaceutically effective absorption.” (PTX 3, at 636-38, 1138; PTX 5, at 542-544, 648). The examiner allowed the claims after that amendment. The concept is to permit the patient to take the drug either with or without food; however, FDA has approved Atelvia® only to be taken with food.
IV. THE TRIAL
At trial, the evidence centered upon whether thq asserted claims of the '459 and '460 patents are invalid due to anticipation or obviousness.
a. Anticipation
“A patent is invalid for anticipation under 35 U.S.C. § 102 if a single prior art reference discloses each and every limitation of the claimed invention.” Allergan, Inc. v. Apotex Inc., 754 F.3d 952, 958 (Fed.Cir.2014). In order to anticipate, the prior art reference must contain “each of the limitations of the claim.” Scaltech, Inc. v. Retec/Tetra, LLC, 178 F.3d 1378, 1383 (Fed.Cir.1999). “Claimed subject matter is' ‘anticipated’ when it is not new; that is, when it was previously known. Invalidation on this ground requires that every element and limitation of the claim was previously described in a single prior art reference, either expressly or inherently, so as to place a person of ordinary skill in possession of the invention.” Sanofi-Synthelabo v. Apotex, Inc., 550 F.3d 1075, 1082 (Fed.Cir.2008). “[T]he dispositive question regarding anticipation is whether one skilled in the art would reasonably understand or infer from a prior art reference that every claim element is disclosed in that reference.” AstraZeneca LP v. Apotex, Inc., 633 F.3d 1042, 1055 (Fed.Cir. 2010) (quoting In re Baxter Travenol Labs., 952 F.2d 388, 390 (Fed.Cir.1991)) (internal quotations and alterations omitted). “[T]he party asserting invalidity due to anticipation must prove anticipation, a question of fact, by clear and convincing evidence.” Orion IP, LLC v. Hyundai Motor Am., 605 F.3d 967, 975 (Fed.Cir. 2010).
“[A] single prior art reference may anticipate without disclosing a feature of the claimed invention if such feature is necessarily present, or inherent, in that reference.” Allergan, Inc. v. Apotex Inc., 754 F.3d 952, 958 (Fed.Cir.2014). “[I]n-herency operates to anticipate entire inventions as well as single limitations within an invention.” Schering Corp. v. Geneva Pharms., 339 F.3d 1373, 1380 (Fed.Cir. 2003). Recognition of an inherent limitation in the prior art by a person of ordinary skill in the art is not required to establish inherent anticipation. Id. at 1377. An inherent limitation is one that is necessarily present and not- one that may be established by “probabilities or possibilities.” See Continental Can Co. v. Monsanto Co., 948 F.2d 1264, 1268-69 (Fed. Cir.1991). That is, “[t]he mere fact that a certain thing may result from a given set of circumstances is not sufficient.” Id.
1. The Brazilian Application
Teva introduced evidence that Brazilian Patent Application, No. BR2001-06601 (DTX 205), anticipated the claimed invention. The Brazilian Application was published on September 9, 2003. No patent has issued. It is prior art under 35 U.S.C. § 103(a) and (b) for both the '459 and the '460 patents. (Joint Stipulation of Facts ¶ 90). The Brazilian Application claimed: “at least one core containing one or more bisphosphonates, at least one core or core coating containing a chelating agent, said core or cores being coated individually or together by a gastroresistant and enterosoluble layer.” (DTX 205, at 9). With respect to bisphosphonates, the Brazilian Application lists risedronate as well as thirteen additional bisphosphonates and their pharmaceutically acceptable salts and hydrates. (Id. at 5-6). Regarding chelat-ing agents, it lists four acceptable chelat-ing agents, including EDTA in either mo-nosodium or disodium form. (Id. at 5). Finally, it disclosed a “gastroresistant and enterosoluble coating” to deliver the che-lating agent “only into the small intestine,” (id. at 3); the application requires bypassing the stomach so that there is no loss of chelating agent in the stomach, (id. at 4). Acceptable coatings include “copolymers of methyl methacrylate — methaerylic acid.” (Id. at 6). The coating “preferably dissolve[s] rapidly in a neutral environment.” (Id.). The bisphosphonate, chelating agent, and delayed release mechanism are combined to “increase[ ] the absorption of bisphosphonates by the action of chelating agents” using two mechanisms: “a) reduction of the formation/solubilization of insoluble complexes of bivalent [calcium and magnesium] ions with bisphosphonates, and b) increase in permeability of the intestinal mucosa.” (Id. at 3).
The parties agree that “somewhere in [the Brazilian Application ] are all of the elements of the asserted claim” except “pharmaceutically effective absorption,” (Tr. 4A.51:16-23). They dispute whether the Brazilian Application disclosed the particular claimed amount of 35 mg rise-dronate sodium combined with the particular claimed amount of 100 mg disodium EDTA.
2. Amount of Risedronate Disclosed
As in the asserted claims, the Brazilian Application used a subset of bisphospho-nates for the purpose of “inhibiting osteo-clast-mediated bone resorption.” (DTX 205, at 2). The Brazilian Application did not instruct the use of a particular amount of risedronate sodium. Rather, it called for an “effective quantity” of any bisphos-phonate, including risedronate sodium, where the “intervals (for example, daily or weekly) ..., the effective quantity, and the rate of release depending on the pathology to be treated, as known to a person skilled in the art.”
It is undisputed that risedronate sodium was “well-known as of 2005 ... [as a] commercially available salt of risedronate.” (Tr. 1 A. 126:4-7). Defendant’s formulation scientist Dr. John Yates — the executive director of clinical research at Merck during development of Fosamax® — testified that a person of ordinary skill at the relevant time would understand the term “effective quantity” of risedronate to be a 35 mg once-weekly dose of risedronate sodium. (Tr. lA.126:2Í-25). The 2002 Actonel® label listed the only approved doses of risedronate as the 35 mg weekly dose of risedronate sodium for osteoporosis, the 5 mg daily dose for osteoporosis, and the 30 mg formulation of risedronate sodium for Paget’s disease. (DTX 185, at 5; Tr. lB.26:4-9). The 35 mg once-weekly dose was the most commonly prescribed regimen of risedronate for osteoporosis. (Tr. 113.25:23-25).
On the other hand, Dr. Stanley Davis — -a professor of pharmaceutical science — testified that the Brazilian Application disclosed the use of substantially less than 35 mg risedronate based on the specification’s statement that, “with this invention we obtain an effective treatment with a small quantity of bisphosphonate compared to the current treatment.” (DTX 205, at 4). Although it acknowledged that small quantities may be useful, the Brazilian Application explicitly suggested selecting an “effective quantity” of any bisphosphonate as “known to a person skilled in the art,” which would include the 5 mg daily and 35 mg weekly dose. Unlike the amount of EDTA, for which it recommended “lower than the known quantities,” the Brazilian Application did not suggest using less than the known “effective quantity” of the bisphosphonate. Consequently, a person of ordinary skill in the art would read the Brazilian Application to disclose as an acceptable choice for a bisphosphonate a weekly dose of 35 mg risedronate sodium.
3. Amount of EDTA Disclosed
It is undisputed that the Brazilian Application did not disclose solely 100 mg EDTA for use in a formulation. Rather, it disclosed a ten-fold range of EDTA to be paired with a bisphosphonate based on relative molarity. (Tr. lA.128:18-24). Dr. Yates opined that the reference taught a person of skill in the art using risedronate to choose between 20 mg -and 175 mg disodium EDTA. (Tr. lA.128:18-24). The claimed amount, 100 mg disodium EDTA, is within the Brazilian Application’s disclosed preferred range for disodium EDTA.
“[I]f the prior art ... discloses only a range of values, and the new claim recites an overlapping but different range, we have said that the prior-art reference must describe the claimed range with sufficient specificity to anticipate the limitation of the claim — a broad prior-art disclosure that encompasses a narrower claimed range is sometimes not enough for anticipation.” In re Haase, 542 Fed.Appx. 962, 965-66 (Fed.Cir.2013) (internal quotation marks and alterations omitted). Particularly where there is “considerable difference between the claimed ... range and the range in the prior art,” there is no anticipation. But a prior art range anticipates a claimed value if “a trial ... reveals] a minimal difference between the [prior art] range ... and the [claimed value], or that one of ordinary skill would interpret [the prior art range] as clearly disclosing [the claimed value] as an acceptable choice within that rangeOS-RAM Sylvania, Inc. v. Am. Induction Tech., 701 F.3d 698, 706 (Fed.Cir.2012). Evidence that the claimed value is not “critical” or that “the claimed method [does not] work[] differently at different points within the prior art range” indicates that a person of ordinary skill would have envisioned that the claimed value was an acceptable choice within the prior art. See ClearValue, Inc. v. Pearl River Polymers, Inc., 668 F.3d 1340, 1345 (Fed.Cir.2012) (finding prior art variable range of “150 ppm or less” anticipated claimed value of 50 ppm where there was no “evidence that different portions of the broad range would work differently [and] no allegation of criticality or any evidence demonstrating any difference across the range.”).
It is uncontested that, for the bisphos-phonate-EDTA formulation to work effectively, the amount of EDTA must be within a certain range: too low a dose of EDTA is insufficient to block calcium from capturing the active ingredient in the fed state, resulting in negligible absorption; too much EDTA will unduly spread the tight junctions in the fasted state, resulting in too much absorption and other undesirable effects. The question is whether the patentee’s selection of a 100 mg EDTA dose from the Brazilian Application’s disclosed range of 20 to 175 mg EDTA was critical to the invention’s effectiveness. Formulation scientist Dr. Yates testified about literature that taught that substantially all of the calcium in a calcium-rich meal would be competitively chelated by 75 to 150 mg EDTA in the.small intestine, (Tr. IB.60:21-61:4; Tr. 1B.62:14-17; see also Tr. 4B.24:16-23). Both Dr. Yates and Dr. John Dillberger — a former director of toxicology at several pharmaceutical companies — opined that far more than 175 mg EDTA would be required to increase absorption via altering the tight junctions in the fasted state. (Tr. 2A.49:3-12; Tr. 4B.89:18-90:13). Consequently, these experts’ reasoning supports an inference that, at the very least, between 75 and 175 nig of disodium EDTA will work effectively-
On the other hand, the patentee Burgio testified that the invention required more precision than simply choosing a dose from the prior art range. He opined that success required balancing interdependent variables such that a formulation would not work unless “the doses of both bis-phosphonate and the chelator ... [were] titrated just properly.” (Tr. 4A.72:11-14). He claimed that the particular dose of EDTA must vary with: the amount of the bisphosphonate; the type of bisphospho-nate; and the location of release.
The weight of the evidence at trial, however, established otherwise; to wit, that the-proportion of bisphosphonate to EDTA does not affect absorption because the two ingredients work independently of each other and are not interdependent. Defendant’s formulation scientist Dr. Yates, Plaintiffs’ toxicologist Dr. Joseph Ro-dricks — a former FDA Deputy Associate Commissioner — and Defendant’s toxicologist Dr. Dillberger all agreed that an increase in the bisphosphonate dose does not require a corresponding increase or decrease in EDTA. CSee Tr. 2B.41:8-20 (“THE COURT: So the amount of EDTA is not necessarily dependent in any way or connected to the amount of risedronate ... it works independently? DR. DILL-BERGER: Independent. DR. RO-DRICKS: Independent. THE COURT: And I see both sides nodding yes to that.”)).
The challenged patents confirm this reasoning. The specification asserts that a formulation will be pharmaceutically effective if: (1) a “weekly oral dosage form contains from about 10 to about 50 mg risedronate,” (DTX 2, '459 patent, col. 7,11. 21-23); (2) “[w]hen the chelating agent is disodium EDTA, the preferred range is from about 55 mg to about 500 mg, preferably from about 75 mg to about 250 mg per unit dose,” (DTX 2, '460 patent, col. 9, 11. 37-41); and (3) it is delivered to the “lower gastrointestinal tract.” The patents encompass a number of “examples [that] illustrate the formulations ... of the present invention,” (DTX 2, '459 patent, col. 19, 11. 18-19), which include embodiments with double the amount of risedro-nate as EDTA, (DTX 2, at Example II, '459 patent col. 20, 11. 35-65 (150 mg rise-dronate sodium and 75 mg disodium EDTA)); far less risedronate than EDTA, (id., at Example IV, col. 22,11. 60-65 (5 mg risedronate sodium and 75 mg disodium EDTA)); and levels of EDTA that vary independently of risedronate, (id., at Example VIII, col. 27, 11. 55-65 (35 mg rise-dronate sodium and 150 mg disodium EDTA)). Despite the fact that the ratio of EDTA to bisphosphonate varies greatly, all embodiments are stated in the specification as exhibiting “pharmaceutically effective absorption.”
Nor did the evidence at trial indicate that a particular level of EDTA was necessary for a particular type of bisphospho-nate. Again, every testifying toxicologist agreed that combining bisphosphonates and chelating agents was “not like a recipe between the two. Because they’re not interacting with each other.” (Tr. 2B.39:1-41:25). Even Plaintiffs’ formulation scientist, Dr. Davis, knew of no evidence that bisphosphonates and EDTA were interdependent. (Tr. 4A.45:7-47:2). The record evidence is clear that EDTA does not interact with the bisphosphonate at the relevant doses. Its role is separate: to block •calcium ions in food from capturing the active ingredient. (Tr. 2B.39:l-40:25).
Moreover, the '459 and '460 patents encompass pharmaceutically effective formulations containing a range of 75 mg to 250 mg disodium EDTA, but every claimed formulation requires “risedronate sodium” and not any other bisphosphonate. Thus, the patents assert that the disclosed range of 75 mg to 250 mg EDTA will work effectively with risedronate sodium. It does not indicate that any particular level of EDTA is critical for each type of bis-phosphonate.
Similarly, the '460 patent asserts that EDTA between 75 mg and 250 mg will produce “pharmaceutically effective absorption.” Every claim of that patent requires release in the “small intestine.” Thus, a range of EDTA is intended to be effective in the small intestine, rather than any particular level of EDTA.
The evidence at trial, including the expert testimony and the patents’ specification, revealed that a wide range of EDTA between 75 and 175 mg will allow the formulation to work as claimed. The formulation does not require specifically calculating the level of EDTA based on the type of bisphosphonate, amount of bisphos-phonate, or location of release within the small intestine. Nor was evidence introduced' showing that levels lower than 75 mg EDTA would be ineffective. In sum, the evidence showed that the claimed amount of 100 mg was not critical compared to the prior art’s disclosure of between 20 and 175 mg EDTA. The clear and convincing evidence at trial “reveal[ed] a minimal difference between the [prior art] range ... and the [claimed value].” OSRAM, 701 F.3d at 706. “[0]ne of ordinary skill would interpret [prior art range] as clearly disclosing [the claimed value] as an acceptable choice within that range ....” Id.
U. Whether a List of Ingredients Anticipates a Combination
The Brazilian Application disclosed the combination of one of approximately fourteen bisphosphonates (or their salts), with one of about four chelating agents (or their salts), and one of about six delayed-release mechanisms. Included in the Brazilian Application’s disclosure were the claimed ingredients, including “risedronate ... and the pharmaceutically acceptable salts and hydrates thereof’; used in combination with a subset of chelating agents, including “EDTA ... in monosodium or disodium form”; and a delayed release mechanism, including “copolymers of methyl methacry-late — methacrylic acid.”
When prior art discloses a list of acceptable ingredients combined with another list of acceptable ingredients for a particular purpose, “[t]he question for purposes of anticipation is therefore whether the number of categories and components in [the prior art] was so large that the combination ... would not be immediately apparent to one of ordinary skill in the art.” Wm. Wrigley Jr. Co. v. Cadbury Adams USA LLC, 683 F.3d 1356, 1362 (Fed.Cir.2012). If the ¿mount of combinations of explicitly named ingredients is a “defined and limited class” and the amounts of the ingredients are within the prior art range, the result will be anticipated. Id. at 1361-62; see also Perricone v. Medicis Pharm. Corp., 432 F.3d 1368, 1377 (Fed.Cir.2005) (“[S]pecific disclosure, even in a list, makes this case different from cases involving disclosure of a broad genus without reference to the potentially anticipating species.”).
The prior art Brazilian Application disclosed a specific and limited number of bisphosphonates by name combined with a specific and limited number of chelating agents and delayed release mechanisms. The particular ingredients and amounts claimed by Plaintiffs were identified as acceptable within the prior art’s disclosed categories and ranges. The number of possible combinations in the Brazilian Application was not “so large that the combination ... would not be immediately apparent to one of ordinary skill in the art.” Nor was evidence adduced that other combinations disclosed would not have been successful for the claimed purpose.
The Brazilian Application disclosed the claimed elements in the same combination, for substantially the same function: an active ingredient to prevent osteoporosis; a chelating agent to chelate calcium ions in the small intestine, and a delayed release mechanism to bypass the stomach. Thus, it does not require combining different disclosures or random selection from unrelated elements in the prior art, rather it “combine[s] [the elements] in the same way as recited in the claim.” Net Money-IN, Inc. v. VeriSign, Inc., 545 F.3d 1359, 1371 (Fed.Cir.2008).
5. Whether “Pharmaceutically Effective Absorption” is Disclosed
The Brazilian Application did not use the term “pharmaceutically effective absorption.” Distinguishing the prior art to overcome the Patent Office’s initial rejection of the patents, the patentee stated that “pharmaceutically effective absorption” requires EDTA be used only to “address the food effect” via chelation, not to increase intestinal permeability because increased permeability would “result in vastly different bisphosphonate absorption and therefore exposure depending on whether the patient is in the fasted state ... or fed state.” (PTX 3, at 1151). Thus, the definition of “pharmaceutically effective absorption” requires: (1) choosing an amount of EDTA sufficient to “significantly bind the metal ions and minerals in food” after a meal; (2) but which is “low enough not to significantly alter absorption” by increasing intestinal permeability; (3) with the result that “absorption is similar with or without food ... [F]ed exposure within about 50% of fasting exposure is expected to be ‘pharmaceutically effective absorption.’ ”
A.“Significantly Bind the Metal Ions in Food ”
The concept of using sufficient EDTA to bind to the metal ions in food is found within the Brazilian Application. It instructed that delivering the formulation of bisphosphonate and chelating agent to the small intestine “eliminate[s] the interaction of [bisphosphonate] with the contents of the stomach,” including the calcium and magnesium ions found in food that bind to bisphosphonate and prohibit the drug from entering the bloodstream. (DTX 205, at 3). The Brazilian Application proposed a solution to reduce the interaction of bis-phosphonate with calcium and magnesium ions: using a chelating agent to “capture[ ] the bivalent ions in preference to the bis-phosphonate, permitting the bisphospho-nate to remain free for absorption by the body.” (Id. at 4). Both parties’ experts agreed that a person of ordinary skill in the art would have understood that the chelation mechanism disclosed in the Brazilian Application was intended to significantly bind metal ions from food in the small intestine so that the bisphosphonate remains free to be absorbed. (Tr. 1A.129:3-17 (Dr. Yates); Tr. 1A.133:9-11; Tr. 4B.87:22-25 (Plaintiffs’ formulation scientist Dr. Davis stating that “the first part of [the Brazilian Application ] is to avoid the interaction of the bisphosphonate with calcium and magnesium. And that would be something say in — well, in the fed state.”)). Although the Brazilian Application did not explicitly discuss the food effect, the clear purpose of the chelation mechanism is to neutralize the metal ions in food that result in decreased absorption of bisphosphonate in the fed state. (Tr. 4B .86:4-25).
B.“Low Enough not to Significantly Alter Absorption ”
The Brazilian Application did not teach this limitation, rather it suggests using EDTA to “increase permeability of the intestinal mucosa.” Although the reference intended to alter absorption, some evidence at trial indicated that the Brazilian Application’s preferred upper limit for disodium EDTA of 175 mg was, in fact, insufficient to alter intestinal permeability, and that the disclosed range was inherently low enough not to “significantly alter absorption.”
EDTA alters absorption of bisphospho-nate when there is sufficient unchelated EDTA to bind to the ions in the tight junctions, widening the pathways between cells. This does not occur when there is sufficient dietary calcium, as in the fed state. (Tr. 2B.68:25-69:3; Tr. 2B.63:18-22). Even in the fasted state, there is a calcium buffer which protects the cell walls from unchelated EDTA. (Tr. 2A.59:13-19). But where the amount of disodium EDTA exceeds both dietary calcium and the cellular calcium buffer, EDTA will harmfully alter intestinal permeability. Dr. Yates and Dr. Dillberger both opined that far more than 175 mg of disodium EDTA on an empty stomach would be required before there would be a substantial increase in intestinal permeability or increase in absorption. (Tr. 2A.49:3-12; Tr. 4B.89:18-90:13). Although Dr. Rodricks contested whether a person of ordinary skill would have known so at the time, he did not dispute that 175 mg would be insufficient to modify the tight junctions. Thus, all of the record evidence indicates that amounts of disodium EDTA less than 175 mg do not substantially alter absorption by increasing intestinal permeability.
C.“Similar Absorption ”
As stated above, a skilled artisan using a formulation containing 35 mg risedronate and between 75 and 175 mg EDTA would not significantly alter absorption but would significantly bind to the metal ions in food. However, it is undisputed that even the claimed amount of 35 mg risedronate and 100 mg EDTA does not always produce “similar absorption” in the fed and fasted state. After the patents were filed, Plaintiffs discovered that they could achieve “similar absorption” using the claimed formulation in the small intestine, but not in the ascending colon. (PTX 352, at s3). Although some of the disclosed embodiments in the Brazilian Application may result in similar absorption in the fed and fasted state, there is insufficient evidence to clearly and convincingly find that any embodiment would necessarily produce the claimed element. See Continental Can Co. v. Monsanto Co., 948 F.2d 1264, 1268-69 (Fed.Cir.1991). Thus, while it is a close question, the evidence does not reach the clear and convincing level that one practicing any disclosed embodiment of the Brazilian Application would inherently produce the claimed element of “phar-maceutically effective absorption.” If the burden of persuasion were different, the outcome might well be different. Here, the Brazilian Application did not anticipate the asserted claims. See Allergan, 754 F.3d at 960-61.
b. Obviousness
“A patent may not issue ‘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 to which said subject matter pertains.’ ” In re Cyclobenzaprine Hydrochloride Extended-Release Capsule Patent Litig., 676 F.3d 1063, 1068 (Fed.Cir.2012) (quoting 35 U.S.C. § 103(a)).
Obviousness is a question of law based on underlying factual findings regarding: the scope and content of the prior art; the differences between the claims and the prior art; the level of ordinary skill in the art; and objective considerations of nonobviousness. See KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 406, 127 S.Ct. 1727, 167 L.Ed.2d 705 (2007) (citing Graham v. John Deere Co. of Kan. City, 383 U.S. 1,17, 86 S.Ct. 684,15 L.Ed.2d 545 (1966)); see also Cyclobenzaprine, 676 F.3d at 1068. Obviousness is analyzed from the viewpoint of a person of ordinary skill in the art, who has “ordinary creativity.” See KSR, 550 U.S. at 421, 127 S.Ct. 1727. “[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. Although common sense directs one to look with care at a patent application that claims as innovation the combination of two known devices according to their established functions, it can be important to identify a reason that would have prompted a person of ordinary skill in the relevant field to combine the elements in the way the claimed new invention does.” KSR, 550 U.S. at 418, 127 S.Ct. 1727. “A court must ask whether the improvement is more than the predictable use of prior art elements according to their established functions.” Id. at 417, 127 S.Ct. 1727.
1. Level of Ordinary Skill in the Art as of April 2005
The parties agree that the level of ordinary skill in the art is an individual with a Ph.D. or M.D. in pharmaceutical sciences with substantial practical experience developing and testing pharmaceutical formulations in humans, and who has access to other professionals in the formulation sciences, gastroenterology, and the treatment of osteoporosis. (Tr. 1A.122:7-14). The Court agrees with and adopts this level of skill in the art and the concomitant description of a skilled artisan.
2. Scope And Content of the Prior Art
A. Skilled Artisan’s Knowledge of the Bisphosphonate Food Effect Problem
It was well-known by the April 2005 effective filing date of the challenged patents that bisphosphonate absorption decreased when taken with a meal because of its interaction with the. calcium in food. (Tr. 1A.109:8-16; PTX 90, at 1743, Table 2 (1994 publication on oral absorption of bis-phosphonates showing about a five-fold decrease when administered with food as compared to the fasted state); PTX 135, at 178 (2000 publication stating that “oral absorption of [bisphosphonates] is diminished when the drug is given with meals, especially in the presence of calcium and iron.”); DTX 185, at 17). For this reason, patients taking any member of the class of bisphosphonates were instructed to fast overnight before administration, and to wait 30 minutes after administration before eating breakfast. (Tr. 1A.112:21-113:2; Joint Stipulation of Facts ¶¶ 48, 50 (Fosamax® 2000); ¶¶57, 61 (Boniva® 2003)).
Some patients found these dosing instructions inconvenient. (Tr. 1A.113:3-15). Other patients did not follow the dosing instructions and, as a result, did not receive an effective dose. (PTX 118, at 491, Figure 2 (1998 comparative research study finding that over 50% of patients administered bisphosphonate incorrectly and in a manner that reduced absorption)). As one inventor testified, “[i]t was well understood ... in the industry ... that indeed this was a problem.” (Tr. 4A.70:24-25).
A skilled artisan would have understood the cause of the food effect. Well before 2005, it was known that “cations [like calcium] will interfere with the absorption of ACTONEL.” (DTX 185, at 17; DTX 208, at 295 (1995 publication stating that “the bioavailability of bisphosphonates is low, presumably a result of their highly charged structure and their tendency to form insoluble salts with polyvalent cations.”); DTX 167, at 280, 283). As Warner Chilcott acknowledged, by 2004, “the current science told us” that the food effect was caused by “divalent cations in food, such as calcium, ... binding] to risedronate in the GI tract making the complex unavailable for absorption.” (Tr. 2B.121:2-10 (Warner’s Fed.R.Civ.P. 30(b)(6) designee Dr. Gary Galletta); Tr. 4A.69:20-23). It was also known that reducing calcium-bisphosphonate interaction was necessary to solve the problem. (Tr. lB.124:22-25 (patentee Richard Dansereáu stating he was interested in calcium concentrations because “it was a known fact that chemically risedronate does chelate calcium”); DTX 185, at 16 (predecessor drug Actonel® label prohibiting patients taking calcium supplements with their dose)). Moreover, the magnitude of the problem was understood: the 1992 Mahé Reference measured the particular concentration of calcium within different locations in the gastrointestinal tract after a meal. (DTX 133, at 413 (comparing ions of calcium and magnesium in the ileum versus the jejunum after a meal)).
The Court finds that, at the time the challenged patents were filed, a person of ordinary skill in the art would have recognized: (1) the problem — that bisphospho-nates were ineffective when taken with food; (2) the cause and magnitude of the problem — that a particular amount of calcium from a meal captured the active ingredient risedronate and prevented it from being absorbed; and (3) the goal — to defeat the food effect by reducing the formation of ealcium-risedronate complexes.
The skilled artisan would have known of one solution — -the use of a calcium chelator to block calcium ions from forming calcium-bisphosphonate complexes — because that solution had been well explored in the literature.
B. EDTA’s Use as a Chelator of Calcium
Long before 2005, many studies had shown how EDTA operated to increase bisphosphonate absorption. The 1991 Jan-ner study (DTX 167, at 283) tested an oral formulation containing a bisphosphonate and “a calcium chelator, EDTA,” in rats and found increased intestinal absorption of the bisphosphonate. He noted that “bisphosphonates form polynuclear complexes with calcium [which] are precipitated as calcium-bisphosphonates” and posited that EDTA, as a chelation agent, would “reduce the formation of insoluble calcium-bisphosphonate and polynuclear complexes and hence, contribute to a better absorption of the bisphosphonates.” (Id. at 280, 283). He also noted an alternative mechanism whereby EDTA bound to the calcium in the intercellular channels of the rat intestine, “directly enhancing intestinal permeability.” Id. The 1994 Lin study expanded on the concept of the chelation property: “EDTA, by sequestration of calcium (or other metals), prevented the formation of a metal-alendronate complex which is poorly absorbed from the gastrointestinal tract.” (DTX 168, at 1745). He also explained the permeability enhancing property: “chelating agents might alter the integrity of the intercellular tight junctions at high doses resulting in an increase in absorption” because “the tight junctions are formed by specific proteins and divalent cations, such as Ca2+ and Mg2+.” (Id.).
AstraZeneca’s International Patent Publication WO 00/61111 connected EDTA’s chelating properties as a possible solution to the “diminished [absorption] when [bis-phosphonate is] given with meals, especially in the presence of calcium.” (DTX 206, at col. 1, 11. 23-24). It suggested using chelating agents like EDTA, as well as various other agents, in combination with bisphosphonates to achieve “enhanced and/or less variable absorption [of] bis-phosphonates,” (id. at col. 4, 11. 4-7), and “allow the patient to take the medicament more conveniently, e.g. together with food intake,” (id. at col. 2,11.15-18).
EDTA’s use as a chelator of calcium was not limited to bisphosphonates. The 1978 Poiger Reference used disodium EDTA as a chelating agent to eliminate the food effect in humans observed with a drug called tetracycline. Like bisphosphonate, absorption of tetracycline is 'greatly reduced in the presence of “the dietary content of metal ions” like calcium because “[t]etracycline forms chelates with calcium ... which impairs permeation of the drug.” (DTX 162, at 131). Using a formulation with an amount of EDTA that is “equivalent as a molar ratio to the amount of calcium” expected in the stomach, Poiger found that absorption of the active ingredient after ingesting calcium-rich milk was “almost equivalent” to absorption when the subjects had fasted. (DTX 162, at 129-30; see also Tr. 1B.11:2-12). Using this equimolar ratio, “the bioavailability of the drug remained constant irrespective of the diet.” (DTX 162, at 131, Table 1 (experiment nos. 2 & 4 showing that tetracycline administered with EDTA showed fed absorption better than 50% of fasting absorption)). Moreover, disodium EDTA administered in the fasted state did not “significantly change absorption of the drug.” (Id. at 129). In other words, even with 250 mg disodium EDTA, there was no enhanced absorption in the fasted state. (Id., Table 1 (experiment nos. 1 & 2 showing no statistically significant increase in absorption of tetracycline administered in the fasted state without EDTA compared to tetracycline administered in the fasted state with EDTA)). This “obviate[d] special directions about diet during therapeutic use of [tetracycline].” A skilled artisan would recognize that Poiger disclosed a formula — an equimolar ratio of EDTA to expected calcium, (Tr. IB.30:13-14) — for a formulation that would significantly bind to metal ions in food without significantly altering absorption, leading to similar bioa-vailability irrespective of diet. (Tr. IB.12:6-13:14).
The Court also notes and restates its findings on the Brazilian Application above regarding the well-known use of EDTA as a calcium chelator to enhance bisphosphonate absorption. See § IV(a), supra. Additionally, both parties’ experts agreed that a person of ordinary skill in the art would have understood that the calcium chelation mechanism disclosed in the Brazilian Application was intended to significantly bind metal ions from food in the small intestine after a meal so that the bisphosphonate remains free to be absorbed. (Tr. 1A.129:3-17 (Dr. Yates); Tr. 1A.133:9-11; Tr. 4B.87:22-25 (Davis)).
3. Objective Considerations
A. Teaching Away
Toxicology literature in the early 1990s indicated that the amount of EDTA required to be useful in the stomach was too high for safe administration to human patients. Before the Brazilian Application was published, the literature taught that the minimum effective oral dose of EDTA that enhanced absorption of bisphosphonate as a chelator of calcium was about 700 mg, scaled to human weight. (Tr. lB.21:19-22). The literature, including Ezra, Lin, and Janner, also concluded that these high oral doses of EDTA were not clinically useful. (DTX 167, at 283; PTX 90, at 1745; PTX 135, at 185). However, in 2003 the Brazilian Application published and distinguished Lin and Jan-ner’s delivery to the stomach using “extremely high [doses] (more than 100 mg/kg of body weight),” from its proposed delivery “only into the small intestine ” using “chelating agents in quantities lower than the known quantities.” (DTX at 3, 6). This prior art proposed a limit of 175 mg EDTA. The Brazilian Application explained that delivery in the small intestine “eliminate[s] the interaction of these [chelating] agents with the contents of the stomach,” where an abundance of calcium ions would otherwise “consume” the che-lating agent before it reaches the small intestine. (Id. at 3). “[R]elease of the chelating agents only into the small intestine permits a reduction in the dosage administered for the desired result, which is increased absorption of the bisphospho-nates.” (Id.).
Dr. Yates confirmed that a skilled artisan in 2005 would have known that delivery in the small intestine, rather than the stomach, would require far less chelating agent because the stomach has a higher concentration of calcium after a meal than the small intestine. (Tr. 1A.131:18-132:2). No expert witness testified to the contrary. Dr. Yates concluded that a skilled artisan would have known that 75 to 150 mg EDTA delivered to the small intestine would be sufficient to effectively chelate dietary calcium. (Tr. 1B.60:21-61:4).
“[W]hen the prior art teaches away from combining certain known elements, discovery of a successful means of combining them is more likely to be non-obvious.” KSR Int’l, Co. v. Teleflex Inc., 550 U.S. 398, 416, 127 S.Ct. 1727, 167 L.Ed.2d 705 (2007). “A reference may be said to teach away when a person of ordinary skill, upon reading the reference, would be discouraged from following the path set out in the reference, or would be led in a direction divergent from the path that was taken by the applicant. A reference does not teach away, however, if it merely expresses a general preference for an alternative invention but does not criticize, discredit, or otherwise discourage investigation into the invention claimed.” Galderma Labs., L.P. v. Tolmar, Inc., 737 F.3d 731, 738 (Fed.Cir.2013). “The degree of teaching away will of course depend on the particular facts; in general, a reference will teach away if it suggests that the line of development flowing from the reference’s disclosure is unlikely to be productive of the result sought by the applicant.” In re Gurley, 27 F.3d 551, 553 (Fed.Cir. 1994). “Where the prior art contains apparently conflicting teachings ... each reference must be considered for its power to suggest solutions to an artisan of ordinary skill considering the degree to which one reference might accurately discredit another ... [T]he-prior art must be considered as a whole for what it teaches.” Medichem, S.A. v. Rolabo, S.L., 437 F.3d 1157, 1165-66 (Fed.Cir.2006) (internal alterations and quotation marks omitted).
Compared to the broad conclusions drawn by Lin and Janner based on delivery of very high doses of EDTA to the stomach, the Brazilian Application made specific distinctions between safe and unsafe levels of EDTA delivered to the small intestine. A person of ordinary skill in the art in 2005 would have understood that significantly lower doses than those used by Janner would be useful for the claimed purpose. Placed in context, Lin and Jan-ner teach only that EDTA “alter[s] the integrity of the intercellular tight junctions at high doses,” (DTX 168, at 1743(Lin)), and that doses higher than 700 mg EDTA are “unsuitable,” (PTX 82, at 283 (Jan-ner)). But the literature does not discourage the use of the far lower doses known to be effective in the small intestine. Nor does it suggest that 100 mg EDTA will be unproductive if released in a location other than the stomach, like the small intestine. Reading the literature as a whole, Lin and Janner do not teach away from the claimed amount of EDTA. See Hoffmann-La Roche Inc. v. Apotex Inc., 748 F.3d 1326, 1331 (Fed.Cir.2014); see Medichem, 437 F.3d at 1165-66 (finding that, where some references broadly suggested claimed compound would not work and others suggested it would work in low concentrations, prior art did not teach away).
Additionally, some of the literature noted the danger of using any amount of EDTA for certain purposes, while other references indicated that EDTA was generally safe. Attempting to reconcile these seemingly contrary conclusions, the Court heard expert testimony from two toxicologists: Dr. Rodricks for the Plaintiffs and Dr. Dillberger for the Defendant. Both experts agreed that none of this research directly tested the safety of the claimed dose delivered in the claimed manner. Although they differed in their ultimate conclusion about whether a skilled artisan would have believed that the claimed amount of EDTA was safe, when the Court posed its own questions to them, they were largely in agreement about what the literature taught in 2005. They agreed that there would be little concern if a dose of EDTA were administered with sufficient food. (Tr. 2B.68:25-69:3). Even without dietary calcium — as in the fasted state— both experts agreed that a skilled artisan would have known that there would always be calcium ions in the digestive tract. (Tr. 2B.69:4-10; Tr. 2B.57:16-58:7; Tr. 2B.78:17-19).
Dr. Dillberger testified that this calcium buffer — in the intestinal cells, the fluid surrounding the cells, and the blood supply to those cells — protects cellular tight junctions from EDTA; it must be depleted before there would be a concern that the tight junctions would be damaged. (Tr. 2A.59:13-19). He opined that a person of ordinary skill as of 2005 would know that these reserves of cations were available for EDTA to chelate, (Tr. 2A.49:3-12), and that merely fasting for a day would not clear the intestinal tract of this reserve of calcium, (Tr. 2B.57:22-58:7). Dr. Rodricks did not dispute that residual calcium in the cells would act as a buffer to protect the tight junctions. (Tr. 2B.69:4-10). Both experts agreed that extremely high doses like 700 mg, 7,000 mg and 35,000 mg, scaled to human weight, depleted the calcium buffer and caused separation of the tight junctions, (Tr. lB.21:19-22), and that very low doses like 5 mg were recognized as so safe in pharmaceutical products that they were listed in the Inactive Ingredient Guide, indicating that FDA'required no additional safety rese