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Merck Sharp & Dohme Corp. v. Actavis Laboratories Fl, Inc.

United States District Court, D. New Jersey

September 28, 2017



          PETER G. SHERIDAN, U.S.D.J.

         This is a patent infringement action brought by Merck Sharp & Dohme Corp. (“Merck” or “Plaintiffs”) against Actavis Laboratories FL, Inc., Andrx Corporation, Actavis Pharma, Inc. and Actavis, Inc. (collectively, “Actavis” or “Defendants”) for filing an Abbreviated New Drug Application (“ANDA”) with the Food & Drug Administration (“FDA”), pursuant to 21 U.S.C. § 355(b)(2), for approval to engage in the commercial manufacture, use or sale of a generic version of Merck's Noxafil® (posaconazole). See 35 U.S.C. § 271(e)(2).

         Merck listed the U.S. Patent No. 5, 661, 151 (“the '151 patent”) with the FDA's Approved Drug Products with Therapeutic Equivalence Applications, commonly known as the Orange Book, in order to market and sell a generic version of Noxafil®. See 21 U.S.C. § 355(b)(1). The '151 patent is directed to the synthesis and clinical use of the antifungal compound posaconazole, which is used for treating or preventing fungal infections.

         Merck alleges that by filing the ANDA application with the FDA, and in particular making a Paragraph IV certification with their filing, Actavis had indicated that Merck's '151 patent is “invalid or will not be infringed by the manufacture, use, or sale of [Actavis'] new drug for which the application is submitted.” See 21 U.S.C. § 355(j)(2)(A)(vii)(IV).

         Accordingly, pursuant to 21 U.S.C. § 355(j)(5)(B)(iii), Merck initiated this suit against Actavis because Actavis' request to market the generic version of Noxafil® is prior to the expiration of the '151 patent.

         In this action, a seven-day bench trial was held in July 2017. During trial, Actavis set forth the defense that filing of the ANDA application does not infringe the '151 patent because the asserted claims 11 and 12 of the '151 patent are invalid. In particular, Actavis asserted that-(i) claim 11 of the '151 patent is invalid because it is inherently anticipated by the European Patent Application EP 0 539 938 A1 (“EP '938”); and (ii) claim 12 is invalid because it is obvious to a person of ordinary skill in the art (“POSA”) in view of the EP '938 reference.

         In contrast, Merck argued that claims 11 and 12 of the '151 patent are valid because Actavis has not shown by a clear and convincing evidence that the asserted claims are rendered inherently anticipated or inherently obvious in view of the EP '938 reference. Further, Merck argued that the EP '938 reference is not a prior art reference under 35 U.S.C. §§ 102(a) and 103(a) because the inventive concepts recited in claims 11 and 12 of the '151 patent were invented on April 14, 1993, and diligently reduced to practice prior to or soon thereafter. As such, antedating the EP '938 reference, published on May 5, 1993.

         Actavis arguably asserted that claim 12 is invalid because it is inherently anticipated by the EP '938 reference; however, the parties later stipulated that claim 12 is not inherently anticipated by the EP '938 reference. (See D.I. 199).

         After careful review and consideration of the evidence presented at the bench trial, the Court finds that Merck has provided that the subject matter recited in claims 11 and 12 of the '151 patent was conceived on April 14, 1993, which was diligently reduced to practice thereafter. Thereby, rendering the EP '938 reference not a prior art reference to the '151 patent. As such, the Court finds that claim 11 of the '151 patent is not invalid under 35 U.S.C. § 102(a); and claim 12 of the '151 patent is not invalid under 35 U.S.C. § 103(a).

         A. Governing Law

         As we know the Leahy-Smith America Invents Act (“AIA”) substantially changed the patent law on September 16, 2011. One such change amended the prior law from a ‘first to invent' to ‘first to file' system except in certain cases. The AIA further provided that the amendments set forth in the AIA would not take effect until eighteen (18) months after enactment (March 16, 2013). This matter arises prior to the effective date. As such, the pre-existing law applies. (See Manual of Patent Examining Procedure (“MPEP”), Section 2159.01); also see AIA 125 Stat. at *293 (Sec. 3(n)(1)).

         B. Procedural Background

         The patent application of the '151 patent was filed on June 2, 1995, which later issued on August 26, 1997, to Schering Corporation (“Schering”). On August 30, 2012, Schering assigned its rights in the '151 patent to Merck.[1] The '151 patent was listed in the FDA's Orange Book in three different New Drug Applications (“NDA”), which are directed to an intravenous infusion solution (300MG/16.7ML (18MG/ML)); oral suspension (40MG/ML); and oral tablet with delayed release (100MG). The NDA, N205053, for the oral tablet with delayed release (100MG), is the one that Actavis seeks approval from the FDA to market and sell a generic version in the United States. (See Complaint (“Compl.”) at ¶ 19; D.I. 1).On November 25, 2013, the FDA approved Merck's NDA N205053, directed to oral tablet with delayed release (100MG), for use in “prophylaxis of invasive aspergillus and candida infections.”[2]

         In its ANDA filing with the FDA, Actavis included a written certification (¶ IV Certification) alleging that the claims of the '151 patent are invalid or otherwise will not be infringed by Actavis' ANDA product. (See id at ¶ 20; see also 21 U.S.C. § 355(j)(2)(A)(vii)(IV)).

         Consequently, on August 6, 2015, Merck initiated this suit against Actavis; alleging that Actavis' request to market the generic version of Noxafil® is prior to the expiration of the '151 patent. As such, infringing Merck's intellectual property rights granted under the '151 patent. (See Id. at ¶¶ 26-30; see also 35 U.S.C. § 271(e)(2)).

         Merck asserted claims 11 and 12 of the '151 patent against Actavis in this suit. (See First Amended Invalidity Contentions at 5; D.I. 67). Independent claim 11 being directed to the compound posaconazole, and dependent claim 12 being directed to a pharmaceutical composition comprising the posaconazole of claim 11 and a pharmaceutically acceptable carrier. Claim 12 depends from claim 11. (Id. at 6). In its invalidity contentions, Actavis asserted, inter alia, that claims 11 and 12 of the '151 patent are invalid because-(i) claim 11 is inherently anticipated by the EP '938 reference (see id at 21); (ii) claim 12 is inherently anticipated by the EP '938 reference (see id at 23); (iii) claim 11 is obvious in view of multiple grounds (see id at 23-34); and (iv) claim 12 is obvious in view of the EP '938 reference (see id 35-36).

         At trial, Actavis bearing the burden to invalidate the asserted claims of the '151 patent, presented mainly expert evidence to show that the asserted claims 11 and 12 of the '151 patent as being invalid as noted above. The experts were-Dr. Paul Ortiz De Montellano; Dr. Stanley Roberts; Dr. Wei Lu; Dr. Gary Glick; Dr. Edwin P. Alyea; and portions of videotaped depositions of Dr. Viyoor M. Girijavallabhan (“Dr. Giri”), Dr. Frank Bennett, and Mr. Frank Lovey.

         On the other hand, Merck defended the '151 patent by arguing that the asserted claims 11 and 12 are not inherently anticipated or rendered obvious in view of the EP '938 reference. Further, Merck argued that the EP '938 reference does not qualify as a prior art reference because the posaconazole compound recited in claim 11 and the pharmaceutical composition recited in claim 12 were conceived before the publication date of the EP '938 reference (May 5, 1993), and diligently reduced to practice soon thereafter. In order to advance these positions, Merck relied on the following witnesses and experts-Dr. Birendra N. Pramanik; Dr. Anil Saksena; Dr. Roland Dolle; Dr. Fredrick P. Guengerich; Dr. Mahmoud Ghannoum; Dr. Kieren Marr; Dr. Giri; Dr. Raymond Lovey; and Dr. Frank Bennett.

         At the end of the trial, the parties submitted proposed findings of fact and conclusions of law, followed by reply papers. (See Pl.'s Findings of Fact (“FoF”), D.I. 200; Def.'s FoF, D.I. 201; Def.'s Conclusions of Law (“CoL”), D.I. 204; Pl.'s CoL, D.I. 205; Def.'s Reply, D.I. 208; Pl.'s Reply, D.I. 209).

         The issues litigated before the Court were whether-(1) Merck can antedate the EP '938 reference by showing that the claimed subject matter of claims 11 and 12 were conceived before the publication date of the EP '938 reference, and diligently reduced to practice soon thereafter; and (2) if the EP '938 reference is a prior art reference to the '151 patent, is claim 11 inherently anticipated by the EP '938 reference under the pre-law; and (3) if the EP '938 reference is prior art, is claim 12 rendered obvious under the pre-law. (See Def.'s FoF at ¶ 3; see also Pl.'s FoF at ¶ 16).

         C. Conventional Technology & Drug Development

         In or around 1993 (the time of the inventive concepts disclosed in the '151 patent) there was a need for broad-spectrum antifungal agents with increased solubility and favorable activity profile for treating systemic fungal infections. In particular, systemic fungal infections such as, Aspergillus, Candida, Cryptococcus and opportunistic infections, needed to be treated. (See the '151 patent, col. 2, ll. 27-32).

         During the early 1990s, when the HIV/AIDS disease was very high, and there were many immune-suppressed patients, medical professionals in this field were aware of the need to cure or treat fungal infections more effectively. (See Plaintiff's Expert, Dr. Kieren Marr's testimony Transcript (“Trans.”) at 1185:19-24, 1195:21-1196:10 (Marr), dated July 19, 2017). Dr. Marr testified that there are two types of fungal infections-local and systemic functions. Distinguishing between them, she stated that a local fungal infection, such as athlete's foot is limited to an external part of the body; but systematic fungal infections involve fungal invasion of more than one organ system, such as the blood, lungs, or brain, which are caused by yeasts and molds such as Aspergillus, Candida, Zygomycetes, Cryptococus, and Coccidioides. Systemic fungal infections being prevalent in persons who have compromised immune systems. (See Trans. at 1191:22- 1194:10 (Marr); see also Pl.'s FoF at ¶¶ 70-73).

         Dr. Marr, “an expert in infection diseases, particularly the pathogenesis, diagnosis and prevention and treatment of fungal infections” (see Trans. at 1188:3-6), testified that one of the drugs available to physicians in the year 1993 to treat people with fungal infections was Amphotericin B, which was administered intravenously. The side effect of this drug was that it caused severe kidney destruction; resulting in fevers and chills. (See Trans. at 1194:16-25 (Marr); see also Pl's FoF at ¶¶ 79, 81).

         Next, Dr. Marr noted that the other conventional drugs included-Flucytosine, Ketoconazole, Fluconazole, and Itraconazole. (See PX 1057). Dr. Marr testified that in 1993, the only antifungal drugs available for physicians to prescribe for systemic fungal infections were the aforementioned drugs. (See Trans. at 1202:3-7). All of these conventional drugs have a broader spectrum than their predecessor, but they have significant side effects. For example, Flucytosine had limited usage because fungal infections became rapidly resistant to this drug (see Trans. at 1196:20-23); Ketoconazole, approved by the FDA in 1981, created toxicities in the liver when it interacted with the P450 enzyme (see Trans. at 1197:1-6; see also Pl.'s FoF at ¶¶ 83, 84); Fluconazole, which was considered very safe, had activity against Candida species, but had no activity against molds (i.e., Zygomycetes) (see Trans. at 1198:19-1199:3, 1200:9-10); and lastly, Itraconazole, approved by the FDA in 1992, was effective against molds (Aspergillus); but Itraconazole was not very effective in treating people with suppressed immune systems, and was not safe for patients with heart defects. (See Trans. at 1200:11-25; see also Pl.'s FoF at ¶ 86).

         Moreover, Dr. Marr testified that in the late 1980s and the early ‘90s there were no FDA approved drugs available to prevent or treat patients that were susceptible to fungal infections, there was only conventional amphotericin B. (See Trans. 1203:24-1204:1). As such, there was a pressing need for a broad spectrum drug that could be administered for preventive use for diabetic patients, AIDS patients and transplant patients. (See Pl.'s FoF at ¶ 88).

         Similarly, Dr. Dolle, Merck's expert in drug discovery and medicinal chemistry (see Trans. at 538:18-21), concurred with Dr. Marr about the ongoing need for antifungal drugs. In 1940s, Benzimidazole, a forerunner of azole class, was introduced in the market, which had weak activity against fungi. (See PX 1017). Then in the 1960s, Miconazole, a topical agent to treat things like fungus and ringworm, was approved by the FDA around 1960s. Thereafter, in 1977, Ketoconazole was approved, which was the first oral active agent. (See Trans. at 727:12-25 (Dolle)). Ketoconazole, the first orally active compound, lead further interest by the scientific community into following up on azoles in treating antifungal infections. (Id. at 728:3-8 (Dolle)).

         Dr. Dolle further noted that developing a new antifungal drug is a long drawn out process. (See PX 1002). He explained that the pre-clinical phase a lead compound is identified, optimized, and then tested in animals. Whereas, under the clinical phase, the lead compound is tested in humans; and the assessment of the lead compound's efficacy and safety in humans is determined, before being approved by the FDA. (See Trans. at 541:25-542:1-7 (Dolle)).

         In summary, Dr. Dolle noted that it is an industry average that around 10, 000 compounds that are synthesized or evaluated for their biological activity under the pre-clinical phase. Only 0.1% percent of those compounds enter the clinical phase, out of which only 10% have a chance of getting FDA approval. (See Trans. at 542:8-23 (Dolle)). Consequently, the entire process may exceed ten (10) years from possessing a lead compound through the clinical phase and obtaining FDA approval. (See Trans. 542:21-543:3 (Dolle)).

         D. Development Of Posaconazole

         In early 1993, Schering performed studies on Compound IIc (i.e., SCH-51048). The research and studies indicated that when Compound IIc was administered to mice, there was a compound within mice's blood that had better antifungal activity than its parent compound (Compound IIc). This suggested to the scientists at Schering, in particular Dr. Saksena, that some metabolite of Compound IIc was more active than the parent compound itself. (See Pl.'s FoF at ¶ 108; citing Trans. at 472:4-19; 1353:16-19; JX 44.0027; JX 44.0036). This active metabolite was called “Metabolite A.”

         Although Dr. Saksena learned about the existence of this active metabolite, Metabolite A, he did not have any idea or mental conception of the structure of this active metabolite. (See Pl.'s FoF at ¶ 114). As such, Dr. Saksena and his colleagues attempted to learn more about the structure of this metabolite by undertaking further research. (Id. at ¶ 117). On April 13 and 14, 1993, Dr. Larry Heimark, a mass spectrometrist, performed serum samples of the antifungally active CF-1 mouse metabolite of Compound IIc. (Id. at ¶ 118; citing JX 7.0003-05). Dr. Birendra Pramanik, a senior mass spectrometrist and Dr. Heimark's supervisor, analyzed the mass spectra provided by Dr. Heimark and wrote down the results of his analysis in his lab notebook. (Id. at ¶¶ 119-120). These results are shown below-

         (Image Omitted)

(See JX 7.0001). Dr. Pramanik's handwritten remarks (above) are difficult to read but in substance the notes state that this structure, as labeled as “SCH 51048 Metabolite, ” is-(i) data of the metabolite sample indicated that the compound is a secondary alcohol; (ii) oxidation occurred at the side chain (X) (annotated in the figure); and (iii) additional work is in progress.

         On the same day, April 14, 1993, Dr. Pramanik discussed his findings and mass spectra with Drs. Saksena and Giri. Based on the evidence before them, Drs. Pramanik, Saksena and Giri perceived that Metabolite A could have any of seven possible structures. These seven possibilities included-two primary alcohols, four secondary alcohols, and one tertiary alcohol. (See Pl.'s FoF at ¶¶ 121-124). “Primary” and “secondary” refer to the specific carbon to which the OH group is attached. (See Def.'s Br. at 4). The tertiary alcohol was quickly ruled out during this meeting, and on April 14, 1993, they decided to synthesize and test each of the six alcohols to determine which one of the six alcohols had antifungal activity. (See Pl.'s FoF at ¶ 127; citing Trans. at 476:13-20 (Saksena); 1145:21-1146:2 (Giri); and 1337:25-1338:2 (Glick)).

         The six alcohols were synthesized as three pairs of racemates (i.e., as three mixtures, each containing a pair of two distinct stereoisomers) for purposes of synthetic convenience, as the three racemates could be more quickly prepared; resulting in an early evaluation of the biological activity of the compounds. (See Pl.'s FoF at ¶¶ 128-129).

         Both posaconazole and SCH-51048 are each single “stereoisomers.” In a general sense, this means that each compound has a corresponding pair compound that has the same atoms, attached in the same way, but with a non-superimposable mirror-image configuration in three-dimensional space, similar to left and right hands. (See Trans. at 60:11-61:17; 62:23-63:23) (Ortiz De Montellano). These mirror-image compounds are denoted as “(R)” and “(S)” forms of the compound. (See Trans. at 62:20-22; 63:24-64:3) (Ortiz De Montellano). The different stereoisomers of a molecule often have different biological activity and/or toxicity. One well-known example of this phenomenon is the drug thalidomide. The (R) form of thalidomide is effective against morning sickness, while the (S) form causes birth defects. (See Trans. at 64:23-65:11) (Ortiz De Montellano). See Def.'s FoF at ¶¶ 11-12.

         The purpose of synthesizing the six alcohols was to test their activity against fungal agents, both in vivo and in vitro, and ultimately determine if any of these compounds could be developed into marketable drugs. (Id. at ¶ 132). To test each of the six alcohols in vivo, each of them would have to be formulated as a pharmaceutical composition containing a potentially antifungally effective amount of posaconazole suitable for administration to laboratory animals suffering from fungal infections. (Id. at ¶ 133).

         The synthesis of the six alcohols, which were determined during the April 14, 1993, meeting between Dr. Giri, Dr. Saksena and Dr. Pramanik, was assigned to Mr. Raymond Lovey. (Def.'s FoF at ¶ 25). Mr. Lovey was tasked to synthesize three racemic mixture, or racemate, (mixtures of two stereoisomers), SCH-55801, SCH-55803, and SCH55805. (Id. at ¶ 26; Pl.'s FoF at ¶ 148). The three pairs of the racemic mixtures are shown below-

         (Image Omitted)

(See Pl.'s FoF at ¶ 180). SCH-55801 and SCH-55803 corresponded to the four secondary alcohols of SCH-51048, and SCH-55805 corresponded to the two primary alcohols of SCH-51048. (Id. at ¶ 181).

         During the April 14, 1993 meeting, Drs. Giri and Saksena provided Mr. Lovey with an outline of the synthetic steps to make the racemates. (See Pl.'s FoF at ¶ 150). Mr. Lovey's five-step synthesis of SCH-55801 started on April 26, 1993 and was completed by May 26, 1993. (Id. at ¶ 154). The five-steps included-(i) dihydroxylation of 2-pentene (step 1); (ii) protection of 2, 3-pentanediol (step 2); (iii) sulfonation of SEM protected 2, 3 pentanediol (step 3); (iv) coupling of triazole core (step 4); and (v) deprotection to remove SEM protecting group, yielding posaconazole and its enantiomer (step 5). (See PX 1010; Pl.'s FoF at ¶ 182-183).

         On May 26, 1993, Mr. Lovey made SCH 55801, posaconazole, as a one-to-one mixture with the R, R isomer. (See Pl.'s FoF at ¶¶ 184-185). A mass spectra analysis done on June 14, 1993 indicated SCH-55801 had the distinctive fragmentation pattern of the secondary alcohol analogs of SCH-51048. (Id. at ¶ 187). The three racemic mixtures Mr. Lovey synthesized were tested in in vitro experiments, which showed that all had activity and that they were more active than SCH-51048. (Id. at ¶ 190).

         After the three racemic mixtures-SCH-55801, SCH-55803 and SCH-55805-were tested for in vitro antifungal activity, Drs. Giri and Saksena directed their team to make the six alcohols in pure form. (Id. at ¶ 197). Dr. Bennett, one of the Schering scientists tasked with making the pure form, began his work on June 30, 1993, and concluded the synthesis of pure posaconazole on August 20, 1993. (Id. at ¶ 200). Dr. Bennett began with synthetic routes to the azole core and the piperazine linker ‘in hand, ' and attached the side chain necessary to make posaconazole as a pure compound. (Id. at ¶¶ 159-160). As such, Dr. Bennett was the first person to make SCH-56592, which was later known as posaconazole, not in a mixture with its RR enantimoer. (Id. at ¶ 199). The in vivo testing showed that SCH 56592 (posaconazole) had the best oral activity, the best pharmacokinetics, and the best efficacy of the six individual stereoisomers. (Id. at ¶ 203).

         By October 18, 1993, a protocol for testing all six secondary and primary alcohol analogs of SCH-51048, including posaconazole, in mice infected with Candida albicans was in place; and testing of the six alcohols as pharmaceuticals began. (Id. at ¶ 209). Between October 18, 1993 and December 21, 1993, posaconazole was tested in vivo, the results were analyzed, and 171, 083 patent application (“'083 patent application”) was filed. (Id. at ¶ 211).

         E. The '151 Patent

         A. Earliest Priority Date

         The parties agree that the earliest priority date of the '151 patent is December 21, 1993. (See First Amended Invalidity Contentions at 6). The '151 patent is a continuation-in-part (“CIP”)[3]application of a PCT application, and the PCT application is a CIP application of the '083 patent application (“'083 patent application”).

         B. Disclosure of the '151 Patent

         The '151 patent is generally directed to the synthesis and clinical use of antifungal compound posaconazole, which is used for treating and/or preventing fungal infections. (See Abstract of the '151 patent). Posaconazole is an azole antifungal, which means it is a particular class of chemical compounds that are known to have antifungal activity. (See Trans. at 7:8-14). The '151 patent discloses antifungal compounds of formula I and pharmaceutical compositions, which are expected to exhibit anti-allergic, anti-inflammatory and immunomodulating activities. The pharmaceutical composition contains a fungicidally effective amount of other antifungal compounds. (Id. at col. 56, ll. 40-67).

         The chemical structure of posaconazole, which shows the arrangement of the atoms within the molecules and which atoms are bonded together, and whether single, double or triple bonds are formed between, is illustrated in claim 11-

         (Image Omitted)

(see the '151 patent, col. 78, ll. 1-20; see also Def.'s Br. at 2; D.I. 162; see also Def.'s FoF at ¶ 9 (“there are three parts to the posaconazole structure, the azole core, the piperazine linker and the side chain.”); see also Pl.'s FoF at ¶ 134). Dr. Dolle, Merck's expert, testified that the chemical structure of the posaconazole compound is a three-dimensional structure, wherein the dashed lines and the bold solid lines, as illustrated above, represent groups behind the plane and coming out of the plane, respectively. (See Trans. 563:24-564:3 (Dolle)).

         The '151 patent further discloses that pharmaceutical compositions are formulated by combining the compound of formula I or an equivalent amount of a pharmaceutically acceptable salt of compound I with a suitable, inert, pharmaceutically acceptable carrier or diluent. Examples of suitable pharmaceutical compositions include solid or liquid compositions for oral administration such as tablets, capsules, pills, powders, granules, solutions, suppositories, troches, lozenges, suspensions or emulsions. (Id. at col. 57, ll. 40-50).

         Further, the '151 patent discloses that a solid carrier can be one or more substances which may act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders or tablet disintegrating agents, or as an encapsulating material. The carrier can also be a finely divided solid which is in admixture with the finely divided active compound. In a tablet form, for example, the active compound is mixed with the carrier that has the necessary binding properties. The carrier is added in suitable proportions such that the tablet is compacted in the desired shape and size. (Id. at col. 57, ll. 45-55).

         During prosecution of the patent application of the '151 patent, the examiner rejected the claimed subject matter. The Applicant amended the then pending claims to include claim term “in vivo” to differentiate over the cited art. (See Image File Wrapper of the '151 patent, Applicant's Arguments/Remarks Made in an Amendment, filed May 24, 1996). This amendment was made in response to patent examiner's rejection mailed on November 22, 1995. Additionally, arguments against the obviousness rejection under 35 U.S.C. § 103 were also made. (Id.)

         After mailing a final rejection on August 21, 1996, the examiner conducted a personal interview with the Applicant's representative. During the personal interview, the enablement rejection under pre-AIA 35 U.S.C. § 112, first paragraph, was discussed, and the Applicants agreed to provide an affidavit demonstrating that enablement exists for use of “in vivo” esters. (See Examiner Interview Summary Record mailed on December 19, 1996).

         Thereafter, the Applicant filed a response to the outstanding Office action with a declaration from Dr. Ashit K. Ganguly, a co-inventor of the '151 patent. In the response, the Applicant essentially argued that based on the specification a POSA would be able to readily determine which of the ester compounds would be soluble or suspendible in a pharmaceutically acceptable aqueous media. (See Applicant's Arguments/Remarks filed on January 29, 1997; citing Declaration of Dr. Ganguly at ¶ 17).

         Further, Applicants noted that they are “amending claim 17 of this application to cover a preferred embodiment, and to recite that such esters of the compounds of the claimed invention have a solubility in a pharmaceutically acceptable media of at least about 1 to about 50 mg/ml.” (Id. at 6). Thereafter, on February 7, 1997, a notice of allowance was mailed by the patent examiner, which was later followed by a corrected notice of allowance on ...

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