UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________
`
`ARGENTUM PHARMACEUTICALS LLC
`Petitioner
`
`v.
`
`ALCON RESEARCH, LTD.
`Patent Owner
`
`
`Patent No. 8,268,299
`Issue Date: September 18, 2012
`Title: SELF PRESERVED AQUEOUS PHARMACEUTICAL COMPOSITIONS
`
`
`
`Inter Partes Review No. IPR2017-01053
`
`
`
`PETITIONER’S REPLY TO PATENT OWNER’S RESPONSE
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`_______________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________
`
`ARGENTUM PHARMACEUTICALS LLC
`Petitioner
`
`v.
`
`ALCON RESEARCH, LTD.
`Patent Owner
`
`
`Patent No. 8,268,299
`Issue Date: September 18, 2012
`Title: SELF PRESERVED AQUEOUS PHARMACEUTICAL COMPOSITIONS
`
`
`
`Inter Partes Review No. IPR2017-01053
`
`
`
`PETITIONER’S REPLY TO PATENT OWNER’S RESPONSE
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`TABLE OF CONTENTS
`
`I.
`
`II.
`
`INTRODUCTION ........................................................................................... 1
`
`ALCON’S POSA IS UNSKILLED ................................................................. 2
`
`III. XIA, SCHNEIDER, AND CHOWAN ALONE OR WITH
`TRAVATAN LABEL® RENDER THE CLAIMS OBVIOUS ..................... 2
`
`A.
`
`Improving Schneider with Xia and Chowan ......................................... 3
`
`1.
`
`2.
`
`3.
`
`Xia expressly teaches the claimed zinc concentrations .............. 3
`
`Omitting EDTA was Obvious ..................................................... 7
`
`Schneider, Xia and Chowan suggest the claimed zinc-
`plus-borate-polyol combination .................................................. 8
`
`B.
`
`The Propylene Glycol and Sorbitol Limitations Were Obvious ......... 12
`
`1.
`
`2.
`
`3.
`
`Alcon reduces a POSA to an automaton to avoid the art ......... 13
`
`Alcon’s “unexpected discoveries” were long-recognized ........ 15
`
`Routine optimization would provide the propylene glycol
`and sorbitol limitations ............................................................. 16
`
`C.
`
`Anionic Species and Buffering Anions Limitations Were
`Obvious ............................................................................................... 17
`
`D.
`
`The pH Limitations Were Obvious ..................................................... 20
`
`1.
`
`2.
`
`A pH within 5.5-5.9 was taught to provide a stable,
`comfortable travoprost solution. ............................................... 20
`
`Reducing pH to reduce unwanted precipitation was
`known and expected. ................................................................. 21
`
`i
`
`
`
`IV. GADD AND THE OTHER PRIOR ART PROVE THE CLAIMS
`OBVIOUS ...................................................................................................... 22
`
`V.
`
`SECONDARY CONSIDERATIONS DO NOT OVERCOME THE
`STRONG CASE OF OBVIOUSNESS ......................................................... 25
`
`A. Alcon Fails To Show Any Long-felt-but-unmet Need Met by
`TRAVATANZ® ................................................................................... 25
`
`B.
`
`Alcon’s Commercial Success Arguments Fail to Rebut the
`Strong Case of Obviousness ................................................................ 27
`
`VI. CONCLUSION .............................................................................................. 28
`
`
`
`ii
`
`
`
`
`TABLE OF AUTHORITIES
`
` Page(s)
`
`Cases
`
`Custom Accessories, Inc. v. Jeffrey-Allen Indus. Inc.,
`807 F.2d 955, 962 (Fed. Cir. 1986) ..................................................................... 2
`
`In re Applied Materials, Inc.,
`692 F.3d 1289 (Fed. Cir. 2012) ..................................................12, 16, 19, 21, 22
`
`In re Beattie,
`974 F.2d 1309 (Fed. Cir. 1992) .......................................................................... 18
`
`In re Chapman,
`357 F.2d 418 (CCPA 1966) ............................................................................ 4, 13
`
`In re GPAC, Inc.,
`57 F.3d 1573(Fed. Cir. 1995) ............................................................................. 22
`
`Iron Grip Barbell Co. v. USA Sports,
`392 F.3d 1317 (Fed. Cir. 2004) .................................................................. 6, 7, 22
`
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398, 418-21 (2007) ............................................................................... 2
`
`Merck & Co., Inc. v. Biocraft Laboratories, Inc.,
`874 F.2d 804 (1989) ........................................................................................ 3, 13
`
`In re Peterson
`315 F.3d 1325 (Fed. Cir. 2003) .......................................................................... 19
`
`Upsher-Smith Labs. v. Pamlab, LLC,
`412 F.3d 1319 (Fed. Cir. 2005) .......................................................................... 17
`
`In re Widmer,
`353 F.2d 752 (CCPA 1965) ............................................................................ 4, 13
`
`In re Woodruff,
`919 F.2d 1575 (Fed. Cir. 1990) .......................................................................... 19
`
`iii
`
`
`
`I.
`
`INTRODUCTION
`
`The claimed formulations contain no novel ingredients, no concentration
`
`ranges not found in the ophthalmic prior art, nor do the ingredients perform any
`
`function not already recognized in the art. Both zinc and borate-polyol complexes
`
`were known to provide preservative efficacy (“PE”), while enhancing the activity
`
`of other included antimicrobial agents. Also known were the potentially
`
`deleterious effects of anionic species, as well as the stability-enhancing effect of
`
`pH in travoprost formulations. By 2006, a POSA was well-motivated to improve a
`
`host of ophthalmic products to avoid BAK, including the well-known travoprost
`
`formulation Travatan®, via inclusion of zinc and borate-polyol complexes to
`
`achieve PE, and would have arrived at the claims of the ’299 Patent via routine
`
`optimization, but-for Alcon’s blocking patents.
`
`Alcon counters with a pedantic POSA focusing solely on most-preferred
`
`embodiments and select working examples, to the exclusion of broader art
`
`teachings and relevant understandings. However, a POSA is a person of ordinary
`
`creativity, and it is not hindsight to optimize using known result-effective-
`
`variables. Alcon also alleges “unknown solutions” to “unexpected discoveries”
`
`that were in fact recognized and understood long before the priority date. None of
`
`Alcon’s arguments nor proffered secondary considerations withstand scrutiny, as
`
`discussed in detail herein.
`
`1
`
`
`
`II. ALCON’S POSA IS UNSKILLED
`The parties seemingly agree on the level of skill in the art, but Alcon
`
`presents a POSA narrowly focused on only select parts of the prior art, unaware of
`
`art-recognized equivalence between polyols, unaware of well-known ionization
`
`behavior of borate-polyol complexes, and unable to routinely optimize preservative
`
`efficacy despite Chowhan’s express teachings. POR, 16-24, 30-41; EX1093 ¶¶8-9.
`
`Contrary to Alcon’s assertion, a POSA is capable of making inferences and is
`
`presumed to know basic knowledge in the field and all pertinent art relating to
`
`ophthalmic formulation. KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 418-21
`
`(2007); Custom Accessories, Inc. v. Jeffrey-Allen Indus. Inc., 807 F.2d 955, 962
`
`(Fed. Cir. 1986).
`
`III. XIA, SCHNEIDER, AND CHOWAN ALONE OR WITH TRAVATAN
`LABEL® RENDER THE CLAIMS OBVIOUS
`
`Before September 2006, a POSA would have been motivated to improve
`
`Schneider’s well-known travoprost ophthalmic formulation (commercialized as
`
`Travatan®) with Xia’s advancement regarding self-preservation using zinc to avoid
`
`BAK and Chowan’s realization that the borates and polyols (already common to
`
`ophthalmic products) provide additional preservative effect. Pet., 8-28. The
`
`Travatan® Label provides further motivation to select the FDA-approved amount
`
`of travoprost. Pet., 28-33. Contrary to Alcon’s assertions (POR, 6-47), it is not
`
`2
`
`
`
`hindsight for a POSA to follow suggestions expressly taught the prior art, making
`
`claims 1, 2, 4-8, 16, 17, 20 and 28 obvious.
`
`Improving Schneider with Xia and Chowan
`
`A.
`Alcon questions why a POSA would modify Schneider with Xia (POR, 8),
`
`yet freely admits that a POSA, looking to improve Schneider to make it BAK-free,
`
`would have looked for a self-preserved formulation useful for a variety of
`
`products. Id., 8-9. This is precisely what Xia provides—namely, using zinc and
`
`optionally an additional preservative
`
`to yield “self-preserved” ophthalmic
`
`compositions that can incorporate a variety of therapeutic agents, while avoiding
`
`the drawbacks of traditional preservatives (such as BAK). EX1003, 4, 13.
`
`Alcon also argues that because certain formulations in Xia “solved the
`
`problem,” a POSA would not have considered any other formulations,
`
`improvements, or optimization. POR, 9-24. Alcon misunderstands the law on
`
`obviousness, and selectively ignores express teachings in the art that contradict its
`
`arguments, as explained below.
`
`Xia expressly teaches the claimed zinc concentrations
`
`1.
`Alcon’s sole focus on Xia’s examples is legal error. “[I]n a section 103
`
`inquiry, the ‘fact that a specific [embodiment] is taught to be preferred is not
`
`controlling, since all disclosure of
`
`the prior art,
`
`including unpreferred
`
`embodiments, must be considered.’” Merck & Co., Inc. v. Biocraft Laboratories,
`
`3
`
`
`
`Inc., 874 F.2d 804, 807 (1989) (citing In re Lamberti, 545 F.2d 747,750 (CCPA
`
`1976)). Merck’s holding dates back over half a century. See In re Widmer, 353
`
`F.2d 752, 769 (CCPA 1965) (“[W]e cannot agree that in order to be a valid
`
`teaching for reference purposes only so much as is shown in the examples of a
`
`patent is available as prior art.”); In re Chapman, 357 F.2d 418, 424 (CCPA 1966)
`
`(“[A] reference can be used for all it realistically teaches, and is not limited to the
`
`disclosures in its specific illustrative examples.”).
`
`This precedent negates Alcon’s entire argument because Xia expressly
`
`teaches zinc ion concentrations of 0.074mM (“about 0.001 wt.%”) and 0.37mM
`
`(“about 0.005 wt.%”), which fall squarely within the zinc concentration range
`
`claimed in the ’299 patent of 0.04-0.4mM. EX1002, ¶50. Nowhere does Xia state
`
`that zinc concentrations below those in the examples are unsuitable for the
`
`compositions at issue here. EX1093, ¶¶10-11; see also EX1048, 123:12-124:14
`
`(Dr. Zhanel admitting he could not find such a statement in Xia).
`
`Improperly limiting a POSA’s appreciation of Xia to its examples, Alcon
`
`asserts Xia teaches two preservation options: (1) “only zinc” or (2) zinc plus
`
`another preservative (“primary preservative agent”). POR, 9,14-19. Completely
`
`ignoring option 2, Alcon asserts that a POSA would not use “only zinc” in
`
`concentrations lower than 0.48mM and would only look to increase zinc to
`
`improve PET. Id., 17-19. However, Alcon’s assertion contradicts its own expert’s
`
`4
`
`
`
`admission that, all else being equal, a POSA would opt for the lowest preservative
`
`concentration that passes PET. EX1045, 51:24-52:10; see also EX1093, ¶12.
`
`Alcon also ignores that zinc at higher concentrations was a known
`
`astringent. ALCON2032, 7089. Even assuming zinc is “safe” at levels up to
`
`0.25% as Alcon suggests (POR, 15), Dr. Majumdar admitted that astringency
`
`wasn’t normally a desired effect. EX1045, 79:9-16. Hence, a POSA would have
`
`been concerned with using too high a level of zinc, and would therefore have
`
`engaged in optimization to find the lowest suitable zinc concentration. EX1093,
`
`¶12.
`
`Alcon’s outdated and inapt zinc references (POR, 19) also fail to support
`
`their assertion that a POSA would avoid zinc concentrations lower than Xia’s
`
`examples. EX1093, ¶18. A POSA would not have relied on any of the references
`
`to assess the potential of zinc to pass PET in an ophthalmic composition because:
`
`1) none of the references tested an ophthalmic composition, and Dr.
`
`Zhanel admitted that non-ophthalmic compositions cannot predict
`
`PET for ophthalmic compositions (EX1048, 114:15-21);
`
`2) the
`
`references performed experiments
`
`far different
`
`than
`
`the
`
`standardized PET used for ophthalmic products (and called for in the
`
`’299 patent) –
`
`5
`
`
`
`a. none of the references measure microorganism concentrations
`
`after 48 hours, yet the ’299 patent shows measurements prior to
`
`7 days do not predict the 7-day PET result;
`
`b. McCarthy (ALCON2123) and Zeelie (ALCON2124) perform
`
`kill tests, which Dr. Zhanel admits cannot be used to predict
`
`PET outcome (EX1048, 50:13-16); and
`
`3) Xia’s Example 18 demonstrates that “only zinc” at 0.48mM has
`
`preservative efficacy against E. coli and P. aeruginosa, contradicting
`
`Dr. Zhanel’s assertions that (i) Winslow (ALCON2122) suggests to a
`
`POSA that E. coli can adapt and beginning at 48 hours zinc (0.5mM)
`
`has reduced antibacterial activity (ALCON2025, ¶36), and (ii)
`
`McCarthy’s unsupported statement that zinc has “little effect against
`
`the troublesome Pseudomonas aeruginosa” suggests to a POSA that
`
`zinc (0.76mM) is ineffective against the microorganism (id., ¶38).
`
`Dr. Xia provides greater detail regarding why a POSA would regard these
`
`references as inapplicable. EX1093, ¶¶13-24.
`
`Additionally, “where there is a range disclosed in the prior art, and the
`
`claimed invention falls within that range, there is a presumption of obviousness.”
`
`Iron Grip Barbell Co. v. USA Sports, 392 F.3d 1317, 1322 (Fed. Cir. 2004)
`
`(citations omitted). To rebut the presumption the patentee must show “(1) [t]hat
`
`6
`
`
`
`the prior art taught away from the claimed invention; or (2) that there are new and
`
`unexpected results relative to the prior art.” Id.
`
`Here, Xia does not teach away from using zinc within the claimed
`
`concentration range; to the contrary, it expressly teaches that concentrations of
`
`0.074mM and 0.37mM are useful. EX1002, ¶50; EX1093, ¶¶10-12. Nor has
`
`Alcon established the claimed zinc concentration range is critical or achieves
`
`unexpected results; indeed, neither of Alcon’s experts could identify any benefit
`
`conferred by the specifically-claimed zinc concentrations. EX1045, 72:11-24;
`
`EX1048, 31:10-33:25. Given Xia’s express disclosure of the ’299 Patent’s zinc
`
`concentrations and no teaching away or unexpected results, these limitations do not
`
`confer patentability. Iron Grip Barbell, 392 F.3d at 1322.
`
`2. Omitting EDTA was Obvious
`Alcon ignores the art’s teachings when it claims that avoiding EDTA is
`
`purely hind-sight driven (POR, 13). To the contrary, EDTA was well-known to
`
`chelate zinc (see Pet., 19), and both Alcon experts admit that a “POSA would
`
`expect [EDTA] to potentially have a deleterious effect on the antimicrobial activity
`
`of zinc.” ALCON2023, ¶28; ALCON2025, ¶31. Further, Xia demonstrates that
`
`EDTA interferes with zinc’s preservative efficacy. EX1003, Examples 11-15,18;
`
`EX1093, ¶¶25-27. Given this teaching and the admissions from Alcon’s experts, it
`
`7
`
`
`
`clearly isn’t hindsight for a POSA to have omitted EDTA in the Xia-Schneider
`
`formulations in order to fully take advantage of zinc’s antimicrobial effect. Id.
`
`3.
`
`Schneider, Xia and Chowan suggest the claimed zinc-plus-borate-
`polyol combination
`
`Alcon’s attempt to focus solely on option 1 (“only zinc”) is a red-herring
`
`(POR, 14-19), as it ignores Xia’s express teaching to combine zinc with another
`
`preservative (EX1003, 4). Indeed, Alcon admits that the POSA would understand
`
`Xia to be teaching the combination of low levels of zinc with an additional
`
`preservative. POR, 9; ALCON2023, ¶29; ALCON2025, ¶26. Alcon’s admission
`
`only reinforces Petitioner’s argument that a POSA would combine zinc with
`
`another preservative agent—in this case, the borate-polyols as taught by Chowan
`
`and already present in both the Xia and Schneider formulations, negating the
`
`patentability of the claims here. EX1093, ¶¶28-38.
`
`Schneider Formulation A already contains boric acid and mannitol.
`
`EX1093, ¶32. Xia likewise teaches the inclusion of borate as a buffer, and polyols
`
`(e.g., propylene glycol) as comfort agents. Id. As admitted by Dr. Majumdar,
`
`polyols are not an uncommon ophthalmic ingredient, and if borate1 and polyols are
`
`
`
`
` 1
`
` “Borate” is simply a generic term used to refer to boric acid and its borate salts.
`
`See, e.g., EX1004, 2:55-61.
`
`8
`
`
`
`both present in a composition they will form borate-polyol complexes. EX1045,
`
`102:5-12, 169:18-170:5.
`
`Given that borate-polyol complexes will already necessarily be present in a
`
`Schneider-Xia improved formulation, a POSA needed look no further than
`
`Chowan to understand that such complexes provide the additional preservative
`
`that Xia contemplates working in conjunction with zinc. EX1093, ¶¶28-31.
`
`Specifically, borate-polyols’ antimicrobial properties qualify them as a “primary
`
`preservative agent” in Xia. EX1045, 203:21-204:8; EX1093 ¶¶22, 31. Further,
`
`Chowan teaches that borate-polyols are effective, yet gentle antimicrobial agents
`
`and “increase the antimicrobial efficacy of other antimicrobial agents when used in
`
`combination” in ophthalmic compositions. EX1004, 1:49-2:12. Therefore,
`
`contrary to Alcon’s assertions (POR, 20-21), a POSA would have had a strong
`
`incentive to use borate-polyol complexes as an additional preservative in view of
`
`Chowan, especially since the Schneider and Xia formulations already have such
`
`complexes present. EX1093, ¶¶32-33.
`
`Alcon wrongly asserts that borate-polyols only act as antifungals. POR, 20-
`
`21; EX1093, ¶34. Chowan expressly states borate-polyols have “antimicrobial
`
`activity” (EX1004, 2:5-9), and both Alcon experts agree
`
`that
`
`the
`
`term
`
`“antimicrobial” covers BOTH bacteria and fungi (EX1045, 23:5-10; EX1048,
`
`41:8-42:25). Additionally, a POSA would not interpret Chowan’s examples as
`
`9
`
`
`
`teaching that the complexes only act as antifungals because (1) the microorganism
`
`levels were measured after 1 hour (not a standard PET time point), and (2) as
`
`admitted by Dr. Zhanel, there is a limit below which bacteria-log-reduction cannot
`
`be measured (EX1048, 59:8-16). This limit was already met by BAK without the
`
`borate-polyol complex, such that the additional antibacterial properties of the
`
`complexes were masked. EX1093, ¶¶35-38.
`
`Furthermore, Alcon’s own product, Systane® Free, refutes Alcon’s
`
`assertions that a POSA would have no reason to think that borate-polyol
`
`complexes work effectively with zinc to provide preservation (POR, 19-20), and
`
`that such a combination would be sufficiently effective against both fungi and
`
`bacteria to pass USP 27 (id., 20-21). Systane® Free was introduced in late 2005,
`
`almost a year before the priority date. EX1008, 283-84. Critically, the Systane®
`
`Free brochure (which according to Alcon published in January of 2006 (EX1008,
`
`283-84)) expressly discloses a preservative system based on zinc and borate-polyol
`
`complexes
`
`(from sorbitol and propylene glycol)
`
`that avoids
`
`traditional
`
`preservatives while meeting USP standards:
`
`10
`
`
`
`
`
`
`
`EX1042, 2; see also EX1041; EX1043; EX1044.2 This brochure was publicly
`
`disseminated to doctors (see EX1112), and identical information was also available
`
`on the internet at least as of May 28, 2006 (EX1110; EX1111).
`
`Amazingly, Alcon fails to acknowledge this product altogether, and its
`
`experts weren’t even aware of it. See EX1045, 151:1-15, 156:19-157:22, 159:2-
`
`16; EX2025, ¶29. Not having been made aware of such clearly relevant
`
`information, Alcon’s experts’ opinions regarding a POSA’s motivation and
`
`reasonable expectation of success in achieving PE with a zinc-borate-polyol
`
`preservative system should be given little weight.
`
`
`
` 2
`
` Exhibits 1041 and 1042 are documents submitted by Alcon to the Patent Office
`
`during prosecution of the ’299 patent. See EX1008, 266, 349.
`
`11
`
`
`
`B.
`Chowhan discloses
`
`The Propylene Glycol and Sorbitol Limitations Were Obvious
`
`that
`
`in ophthalmic
`
`formulations, borate-polyol
`
`complexes are buffers that have “increased antimicrobial activity as compared to
`
`boric acid or its salts” and which enhance the antimicrobial activity of other such
`
`agents when used in combination. EX1004, 2:5-12; EX1093 ¶39. Chowan directs
`
`a POSA to preferred polyols of “mannitol, glycerin, propylene glycol, and
`
`sorbitol” and mixtures of these polyols for making the complexes, as well as
`
`concentration ranges of the complexes that are even narrower than what Alcon
`
`claims. EX1004, 3:4-6,10-12,43-46; EX1093 ¶39. It also teaches that optimum
`
`amounts of the complexes may be readily determined by a POSA. EX1004, 3:43-
`
`52, 9:32-64; EX1093 ¶39. Only Alcon’s lifeless POSA would fail to understand
`
`from Chowan that the types and amounts of polyols may be adjusted to optimize
`
`both buffering and antimicrobial activity of the complexes in the formulations. In
`
`re Applied Materials, Inc., 692 F.3d 1289, 1297 (Fed. Cir. 2012) (“[T]he prior art
`
`need not provide the exact method of optimization for the variable to be result-
`
`effective. A recognition in the prior art that a property is affected by the variable is
`
`sufficient to find the variable result-effective.”).
`
`Moreover, despite Alcon claiming a POSA would need a particular reason to
`
`select “propylene glycol and sorbitol over other polyols” and “instead of mannitol”
`
`(POR, 36-37), the ’299 Patent itself never excludes mannitol, and instead expressly
`
`12
`
`
`
`includes mannitol compositions (that are free of sorbitol) within the invention
`
`(EX1093, ¶¶51-54). In regards to Alcon’s claimed “unexpected discoveries”
`
`(POR, 24-25, 31-33), these were in fact recognized and understood long before the
`
`priority date, as discussed further below.
`
`Alcon reduces a POSA to an automaton to avoid the art
`
`1.
`Alcon’s POSA is little more than an automaton that ignores the teachings of
`
`Chowhan to only focus on particular working examples. POR, 35-38; EX1093
`
`¶¶40-41, 49-50. For example, Alcon claims a POSA “would have selected
`
`mannitol – not propylene glycol or sorbitol – as a starting point for a proposed
`
`composition” because Chowhan described mannitol as “most preferred” and used
`
`mannitol in working examples. POR, 37; EX2023, ¶85. This assertion is both
`
`legally and factually incorrect. EX1093, ¶50; Merck, 874 F.2d at 807; In re
`
`Widmer, 353 F.2d at 769; In re Chapman, 357 F.2d at 424. Further, a POSA would
`
`have understood that Alcon previously offered for sale a preservative system with
`
`zinc and borate-polyol complexes from sorbitol and propylene glycol. Supra, pp.
`
`10-11.
`
`Similarly flawed is Alcon’s demand that a POSA would need a particular
`
`reason to select “propylene glycol and sorbitol over other polyols” and “instead of
`
`mannitol.” POR, 36-37. In addition to ignoring Chowhan’s recitation of
`
`propylene glycol and sorbitol as “preferred,” this argument is contradicted by the
`
`13
`
`
`
`claims and multiple compositions “of the invention” of the ’299 Patent. The patent
`
`claims do not exclude other polyols, and the ’299 Patent highlights compositions
`
`that include mannitol but not sorbitol as well as one omitting propylene glycol as
`
`“representative of the [’299] invention.” EX1001, 15:41-55, 19:12-32, 20:12-34;
`
`EX1093, ¶¶51-54. Thus, the inventors as of the filing of the ’299 Patent
`
`considered mannitol-containing compositions
`
`(sans sorbitol), as well as
`
`compositions omitting propylene glycol, part of their invention. EX1093, ¶54.
`
`Alcon’s strictures on a POSA are thus inconsistent with what is claimed and
`
`described in the ’299 Patent, which further negates any argument that Chowan’s
`
`teachings are somehow inconsistent with the ’299 Patent invention.
`
`Alcon’s arguments are undercut by the ’299 Patent claims in another way as
`
`well. While Alcon asserts Chowhan teaches “a broad range of possible polyol
`
`concentrations” (POR, 31), Chowhan actually teaches a concentration of borate-
`
`polyol complexes (“preferably between about 1.0 to about 2.5 wt.%”)(id., 3:43-46)
`
`much narrower than provided in claims 1-13 and 15-21 of the ’299 Patent (either
`
`0.35%-4.5% w/v or 0.75%-3.7% w/v)(EX1093, ¶¶55). Further, the only examples
`
`covered by claims of the ’299 Patent do not span the wide ranges of these claims.
`
`EX1093, ¶56. Only by reliance on the same prior art (e.g., Chowhan) that Alcon
`
`now asserts is deficient can Alcon attempt to justify these far broader ranges. Id.
`
`14
`
`
`
`Alcon’s “unexpected discoveries” were long-recognized
`
`2.
`Alcon alleges the ’299 Patent inventors discovered that the selection and
`
`respective concentrations of, e.g., propylene glycol versus sorbitol/mannitol was
`
`“unexpectedly important to controlling the amount of anions in the composition.”
`
`POR, 24-25, 31-33; EX2023, ¶¶82-84, 92-93. Figures 1-3 of the patent are offered
`
`as evidence of the “discovery” because “sorbitol has a much higher tendency to
`
`form anionic species in the presence of boric acid, compared to propylene glycol.”
`
`EX1001, 6:58-7:16.
`
`However, Alcon’s “discoveries” merely reiterate well-known properties of
`
`polyols. Complexing boric acid with sorbitol and mannitol was well-known to
`
`significantly increase acidity (EX1099, 2524), whereas complexing with propylene
`
`glycol was understood to provide a relatively minor increase (EX1100, 67).
`
`EX1093, ¶¶42-45. Such adjustment of acidity goes hand-in-hand with adjusting
`
`buffering. EX1093, ¶¶47-48. The ’299 Patent’s NaOH-addition studies allegedly
`
`showing the inventor’s discoveries (i.e., Figs. 1-3), merely mimic prior-art studies
`
`of borate-polyol complexes involving the same polyols. For example, figure 1
`
`from the patent shows no significant difference between boric acid-mannitol and
`
`boric acid-sorbitol solutions—unsurprising given that Dawber (EX1099) teaches
`
`there were no major differences between sorbitol and mannitol in complexing boric
`
`acid. EX1093, ¶46. Similarly, figures 1-3 show no significant change provided by
`
`15
`
`
`
`propylene glycol even when included along with sorbitol, likewise consistent with
`
`the prior-art. Id. Thus, Alcon’s alleged unexpected discoveries are merely
`
`regurgitations of a POSA’s prior-art knowledge.
`
`3.
`
`Routine optimization would provide the propylene glycol and
`sorbitol limitations
`
`Chowhan expressly contemplates a POSA adjusting the type and relative
`
`concentration of each polyol with boric acid to optimize antimicrobial activity.
`
`EX1004, 2:5-12, 3:4-6&10-13, 9:32-64; Pet., 15-17; EX1002, ¶¶47-48, 54, 60-62;
`
`EX1093, ¶¶39, 49-50. A POSA viewing Chowhan would have recognized that the
`
`selection and concentration of each polyol achieves a recognized result—both anion
`
`concentration and antimicrobial activity—in a predictable fashion not only because
`
`Chowhan warned of potential interactions of borate-polyol complexes, but also
`
`because a POSA understood how to control anions via the selection and relative
`
`concentration of each polyol. EX1093, ¶¶39, 48. Accordingly, a POSA’s arrival at
`
`the particular polyols and specific concentrations for each to form beneficial borate-
`
`polyol complexes in a zinc-containing ophthalmic solution to achieve preservative
`
`efficacy is simply routine optimization. EX1093, ¶¶39, 49-50; Applied Materials,
`
`692 F.3d at 1297 (“[T]he prior art need not provide the exact method of
`
`optimization for the variable to be result-effective. A recognition in the prior art
`
`that a property is affected by the variable is sufficient to find the variable result-
`
`effective.”).
`
`16
`
`
`
`C. Anionic Species and Buffering Anions Limitations Were Obvious
`Alcon asserts that the ’299 Patent claims would not have been obvious
`
`because the claimed anionic species and multivalent buffering anion (collectively,
`
`“Anionics”) concentration ranges would not have been obvious. POR, 24. Yet,
`
`simply by following prior art guidance to use ophthalmic formulations with
`
`minimal Anionics and optimizing them for self-preservation that passed regulatory
`
`standards, a POSA would have arrived at a formulation with the claimed
`
`concentrations of zinc, borate-polyol complexes, and Anionics. Alcon has failed to
`
`establish any criticality to the claimed Anionic ranges, rendering them useless for
`
`establishing a patentable distinction over the prior art. EX1093, ¶¶68-77.
`
`Contrary to Alcon’s suggestion (POR, 25-26), the prior art motivated the
`
`POSA to combine zinc and borate-polyol formulations having minimal or even no
`
`other Anionics. To begin with, none of the prior art formulations require any
`
`Anionics, save borate-polyols. EX1093, ¶¶70-73; Pet., 18-19. Anionics such as
`
`those Alcon points to in Xia (e.g., phosphate, NaCl) are described as optional. Id.
`
`Legally, disclosure of formulations with optional ingredients equates to a
`
`disclosure of formulations without the optional ingredients. Upsher-Smith Labs. v.
`
`Pamlab, LLC, 412 F.3d 1319, 1323, (Fed. Cir. 2005)(holding that a reference
`
`disclosing optional inclusion of a component teaches compositions that do and do
`
`not contain that component). Where, as here, the art suggests a combination of
`
`17
`
`
`
`references, even if for a different reason than patentee’s reason, limiting a
`
`component not required by those references does not make the combination non-
`
`obvious. In re Beattie, 974 F.2d 1309, 1312 (Fed. Cir. 1992)(“law does not require
`
`that the references be combined for reasons contemplated by the inventor”).
`
`Because a POSA’s routine optimization of preservative efficacy of the
`
`combined Xia/Schneider/Chowhan formulation would have led to the claimed
`
`borate/sorbitol/propylene glycol concentrations that satisfy USP27, the Anionic
`
`limitations would also necessarily have been achieved through that same
`
`optimization process. As explained above, Xia and Chowhan make clear,
`
`respectively, that zinc and borate-polyol concentrations were known result-
`
`effective variables for preservation. Supra, 17. Given that optimization of the
`
`combined formulation begins without any significant level of Anionics present
`
`other than borate-polyol, a POSA would not have incorporated excipients that
`
`lowered preservative efficacy to unacceptable levels. EX1093, ¶¶76-77. Further,
`
`Chowhan’s admonition about the deleterious effect of phosphate—and by
`
`extension other Anionics (Pet., 19-20)—would also have dissuaded a POSA from
`
`incorporating Anionics into formulations that already lacked them (especially
`
`where nonionics, such as glycerol, were known substitutes for ionics like sodium
`
`chloride for achieving other desirable properties, such as tonicity, for example).
`
`EX1093, ¶¶73-74. Where a POSA knows to optimize properties—such as
`
`18
`
`
`
`preservative efficacy and comfort—by adjusting result-effective variables that will
`
`result in a formulation meeting all of the claim limitations (e.g., levels of zinc,
`
`borate-polyol, and Anionics), such claims are obvious. Applied Materials, 692
`
`F.3d at 1295-97 (finding composition obvious through routine experimentation
`
`even where multiple result-effective variables were optimized simultaneously).
`
`Lastly, the claimed Anionic concentration ranges provide no patentable
`
`distinction because Alcon has neither argued nor shown the criticality of these
`
`ranges. When prior art ranges overlap with or are near claimed ranges, the latter
`
`are obvious absent evidence showing criticality commensurate with the range. In
`
`re Woodruff, 919 F.2d 1575, 1578 (Fed. Cir. 1990); In re Peterson 315 F.3d 1325,
`
`1330-31 (Fed. Cir. 2003). Alcon shows no evidence that any anions other than the
`
`borate-sorbitol complexes
`
`themselves were
`
`in any way problematic for
`
`preservative efficacy, except possibly phosphate and citrate. EX1093, ¶74.
`
`However, the prior art recognized concerns with phosphate and citrate. Pet., 19-
`
`20. In addition, phosphate and citrate were each only tested at a single
`
`concentration in examples having less zinc than TravatanZ and lacking a borate-
`
`polyol complex altogether. EX1001, 24:29-25:29; EX1093, ¶74. Similarly,
`
`Alcon’s zinc formulation with a concentration of 34.2mM NaCl (well above the
`
`claimed <15mM), passed USP PET. Id. These results undermine any contention
`
`19
`
`
`
`that the specifically-claimed Anionics range is “critical” to the invention, rendering
`
`the sweeping Anionics limitations obvious.
`
`D. The pH Limitations Were Obvious
`Alcon asserts the art teaches away from the claimed pH range due to alleged
`
`irritation, yet fails to cite any evidence regarding such suspected irritation. POR,
`
`41-42; EX1093, ¶63. Alcon further claims the antimicrobial activity provided by
`
`pH reduction is merely a conclusory statement, and no optimizable property for a
`
`travopost formulation relied on pH reduction. POR, 42-45. Alcon argues such a
`
`ra
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