Ex Parte Sawhney et al

Patent Trial and Appeal BoardApr 25, 2016

12485192 (P.T.A.B. Apr. 25, 2016)

UNITED STATES PATENT AND TRADEMARK OFFICE UNITED STATES DEPARTMENT OF COMMERCE United States Patent and Trademark Office Address: COMMISSIONER FOR PATENTS P.O. Box 1450 Alexandria, Virginia 22313-1450 www.uspto.gov APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO. 12/485,192 06/16/2009 Amarpreet S. Sawhney 3516.28US02 2803 62274 7590 04/25/2016 DARDI & HERBERT, PLLC Moore Lake Plaza, Suite 205 1250 East Moore Lake Drive Fridley, MN 55432 EXAMINER SHOMER, ISAAC ART UNIT PAPER NUMBER 1612 MAIL DATE DELIVERY MODE 04/25/2016 PAPER Please find below and/or attached an Office communication concerning this application or proceeding. The time period for reply, if any, is set in the attached communication. PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE __________ BEFORE THE PATENT TRIAL AND APPEAL BOARD __________ Ex parte AMARPREET S. SAWHNEY and WILLIAM H. RANSONE II __________ Appeal 2013-010631 Application 12/485,192 Technology Center 1600 __________ Before LORA M. GREEN, JEFFREY N. FREDMAN, and JACQUELINE T. HARLOW, Administrative Patent Judges. FREDMAN, Administrative Patent Judge. DECISION ON APPEAL This is an appeal1 under 35 U.S.C. § 134 involving claims to a synthetic biocompatible polymeric hydrogel for delivering a therapeutic agent to an eye. The Examiner rejected the claims as failing to comply with the written description requirement, as anticipated and as obvious. We have jurisdiction under 35 U.S.C. § 6(b). We reverse and enter New Grounds of Rejection. 1 Appellants identify the Incept, LLC (see App. Br. 3). Appeal 2013-010631 Application 12/485,192 2 Statement of the Case Background “There are a variety of serious eye diseases that need treatment with a drug regimen. Described herein are hydrogels that can be formed in situ on a tissue to deliver drugs” (Spec. 3, ll. 12–13). The Claims Claims 33–37, 40, 41, and 43–49 are on appeal. Independent claim 33 is representative and reads as follows: 33. A synthetic, biocompatible polymeric hydrogel for delivering a therapeutic agent to an eye comprising: a first synthetic precursor covalently crosslinked to a second synthetic precursor to form the biocompatible hydrogel, a therapeutic agent in a particulate form free of encapsulating materials and being in direct contact with the hydrogel that is released from the hydrogel during a period of time that is at least about two days, wherein, before crosslinking, the first precursor and/or the second precursor comprise a water-degradable group, wherein the hydrogel is internally covalently crosslinked and is low-swelling, as measurable by the hydrogel having a weight increasing no more than about 50% upon exposure to a physiological solution for twenty-four hours relative to a weight of the hydrogel at the time of formation, and wherein the hydrogel is water-degradable, as measurable by the hydrogel being dissolvable in vitro in an excess of water by degradation of the water-degradable group. Appeal 2013-010631 Application 12/485,192 3 The Issues A. The Examiner rejected claims 33–37, 40, 41, and 43–48 under 35 U.S.C. § 112, first paragraph as failing to comply with the written description requirement (Ans. 3). B. The Examiner rejected claims 33–35, 37, 40, 41, 44, and 49 as anticipated under 35 U.S.C. § 102(b) by Harris2 (Ans. 3–6). C. The Examiner rejected claim 36 under 35 U.S.C. § 103(a) over Harris and Nagaoka3 (Ans. 7–8). D. The Examiner rejected claims 43, 45, and 46 under 35 U.S.C. § 103(a) over Harris and Jain4 (Ans. 8–9). E. The Examiner rejected claims 45 and 47 under 35 U.S.C. § 103(a) over Harris, Jain, and Al-Aswad5 (Ans. 9–10). F. The Examiner rejected claims 45 and 48 under 35 U.S.C. § 103(a) over Harris, Jain, and Guyer6 (Ans. 10–11). A. 35 U.S.C. § 112, first paragraph, written description The Examiner finds that “the phrase ‘direct contact’ does not appear in the instant specification” and that “[i]t is unclear where the term ‘direct contact’ is supported” (Ans. 3). 2 Harris, US 2004/0076602 A1, published Apr. 22, 2004. 3 Nagaoka et al., US 4,424,311, issued Jan. 3, 1984. 4 Jain et al., Lessons from phase III clinical trials on anti-VEGF therapy for cancer, 3(1) NATURE CLIN. PRACTICE ONCOLOGY 24– 40 (2006). 5 Al-Aswad, Another Role for Avastin? Neovascular Glaucoma, REV. OPHTHALMOLOGY ONLINE 1–5 (June 2006). 6 Guyer, US 2003/0171320 A1, published Sept. 11, 2003. Appeal 2013-010631 Application 12/485,192 4 The issue with respect to this rejection is: Does the evidence of record support the Examiner’s finding that the phrase requiring the therapeutic agent to be in “direct contact” with the hydrogel lacks descriptive support? Findings of fact 1. The Specification does not recite the phrase “direct contact” ipsis verbis (Spec. generally). 2. The Specification teaches that “[t]he functional polymer along with bioactive agent, with or without encapsulating vehicle, is administered to the host along with equivalent amount of crosslinker and aqueous buffers” (Spec. 35, ll. 10–12). 3. Example 1 of the Specification teaches “Drug Incorporation into Hydrogel,” as follows Two precursors and a diluent were prepared. The first precursor was an 8-armed polyethylene glycol with a succinimidyl glutarate on the terminus of each arm . . . . It was provided as a powder . . . . The second precursor was trilysine in an 0.2 M sodium phosphate buffer at pH 8. A diluent for the first precursor was prepared to be 0.01 M sodium phosphate, pH 4.8. A drug (as indicated in Examples below) was mixed into drug into diluent, and about 200 l of the drug/diluent was drawn into a 1 ml syringe. 66 mg of the first precursor powder was placed into a separate 1 ml syringe. The two syringes were attached via a female-female luer connector, and the solution was injected back-and-forth until the powder was completely dissolved. The second precursor in its solution was drawn (200 l) into a third syringe. With another female-female luer connector, the first and second precursors were thoroughly mixed. The mixed solution was drawn into one of the syringes . . . allowing a suitable reaction time . . . Appeal 2013-010631 Application 12/485,192 5 (Spec. 48, l. 13 to 49, l. 1). 4. Example 4 of the Specification teaches that “[n]ifedipine has a water solubility of less than 1 mg/ml . . . . It was loaded into a hydrogel as per Example 1” (Spec. 49, l. 24 to 50, l. 2). Principles of Law “[I]t is the specification itself that must demonstrate possession. And while the description requirement does not demand any particular form of disclosure, or that the specification recite the claimed invention in haec verba, a description that merely renders the invention obvious does not satisfy the requirement.” Ariad Pharms., Inc. v. Eli Lilly and Co., 598 F.3d 1336, 1352 (Fed. Cir. 2010) (internal citations omitted). Analysis The phrase at issue in claim 1 is “a therapeutic agent in a particulate form free of encapsulating materials and being in direct contact with the hydrogel,” and specifically, the limitation “direct contact.” Appellants do not identify explicit support in the Specification for the term “direct contact” (FF 1). Instead, Appellants contend that “it stands to reason than an agent in a hydrogel that is introduced without an encapsulating material would therefore be in direct contact with the hydrogel. Since the agent is in the hydrogel and is not surrounded by an encapsulating material it would therefore have contact with the hydrogel” (App. Br. 7). We agree. The Specification explicitly teaches “[t]he functional polymer along with bioactive agent, with or without encapsulating vehicle” (FF 2). Further, the Specification teaches, in Example 1, a hydrogel of Appeal 2013-010631 Application 12/485,192 6 nifedipine wherein the drug is mixed back-and-forth with powder of a first precursor until the powder is completely dissolved, followed by addition of a second precursor in solution, and thorough mixing of the first and second precursors with allowing suitable reaction time (FF 3). We agree that the Example 1 process for drug incorporation into hydrogel provides possession of “direct contact” because the process necessarily result in “direct contact” of the therapeutic agent with the hydrogel. Conclusion of Law The evidence of record does not support the Examiner’s finding that the phrase requiring the therapeutic agent to be in “direct contact” with the hydrogel lacks descriptive support. B. 35 U.S.C. § 102(b) and 35 U.S.C. § 103(a) The Examiner finds that “Harris, Figure 1, teaches what appears to be an example of the drug in particulate form” (Ans. 4). For the obviousness rejections, the Examiner relies upon Harris to teach drugs in particulate form. Appellants contend that “there is no evidence that the circle in Figure 1 is a drug particle” (Ans. 14). We find that Appellants have the better position. Patent drawings are not necessarily to scale. In re Nash, 230 F.2d 428, 431 (CCPA 1956). Moreover, Figure 1 does not show that the drug is necessarily in particulate form, rather than in an emulsion, or in some other liquid form. “Inherency . . . may not be established by probabilities or possibilities. The mere fact that a certain thing may result from a given set of circumstances is not Appeal 2013-010631 Application 12/485,192 7 sufficient.” MEHL/Biophile Int’l. Corp. v. Milgraum, 192 F.3d 1362, 1365 (Fed. Cir. 1999). We, therefore, reverse the Examiner’s anticipation and obviousness rejections. We enter the following New Grounds of Rejection. New Grounds of Rejection Under the provisions of 37 C.F.R. § 41.50(b), we enter the following new grounds of rejection. Claims 33–35, 37, 40, 41, 44–46, and 49 are rejected under 35 U.S.C. § 103(a) over Harris and Shalaby.7 Claim 36 is rejected under 35 U.S.C. § 103(a) over Harris, Shalaby, and Nagaoka. Claims 43 and 45–48 are rejected under 35 U.S.C. § 103(a) over Harris, Shalaby, Jain, and Al-Aswad. 35 U.S.C. § 103(a) over Harris and Shalaby The issue is: Does the combination of Harris and Shalaby render claims 33 and 49 obvious? Findings of Fact 5. Harris teaches hydrolytically degradable gels of crosslinked poly(ethylene) glycol (PEG) structures. Addition of water causes these crosslinked structures to swell and become hydrogels. The hydrogels can be prepared by reacting two different PEG derivatives containing functional moieties at the chain ends 7 Shalaby, US 6,413,539 B1, issued July 2, 2002. Appeal 2013-010631 Application 12/485,192 8 that react with each other to form new covalent linkages between polymer chains. The PEG derivatives are chosen to provide covalent linkages within the crosslinked structure that are hydrolytically degradable. Hydrolytic degradation can provide for dissolution of the gel components and for controlled release of trapped molecules, including drugs . . . . The hydrolysis rates can be controlled . . . to provide substantially precise control for drug delivery in vivo. (Harris, Abstract). 6. Harris teaches that “[a] specific example of the one-step method for making a PEG hydrogel having hydrolytically unstable carboxylate ester linkages W formed by the reaction of PEG carboxylic acid and PEG hydroxyl groups Z and Y, respectively, is shown by the following equation: ” (Harris ¶ 45). 7. Harris teaches that: Weak chemical linkages are introduced into the hydrogel that provide for hydrolytic breakdown of the crosslinks and release of drug molecules that can be trapped within the matrix. The gels break down to substantially nontoxic PEG fragments that typically are cleared from the body . . . . Examples of hydrolytically unstable linkages include carboxylate ester, phosphate ester . . . orthoesters. (Harris ¶¶ 26–27). 8. Harris teaches that “[t]he rate of release of drug molecules trapped within the matrix is controlled by controlling the hydrolytic Appeal 2013-010631 Application 12/485,192 9 breakdown rate of the gel . . . the ester linkages of the gel will hydrolyze with a half life of about 4 days” (Harris ¶¶ 32–33). 9. Harris teaches that: The rate of release of drug molecules trapped within the matrix is controlled by controlling the hydrolytic breakdown rate of the gel. The hydrolytic breakdown rate of the gel can be adjusted by controlling the degree of bonding of the PEGs that form the hydrogel matrix. A multiarmed PEG having 10 branches or arms will break down and release drug molecules more slowly than a 3 armed PEG . . . . Typically, increasing the n value (the number of methylene groups) in the above structure decreases the hydrolysis rate of esters and increases the time required for the gel to degrade. If n in the above example is 1, then the ester linkages of the gel will hydrolyze with a half life of about 4 days at pH 7 and 37o C. If n is 2, then the half life of hydrolytic degradation of the ester linkages is about 43 days at pH 7 and 37o C. (Harris ¶¶ 32–33). 10. Harris teaches that “[t]he PEG polymer can be covalently attached to insoluble molecules to make the resulting PEG-molecule conjugate soluble. For example . . . the water-insoluble drug taxol, when coupled to PEG, becomes water soluble” (Harris ¶ 7). 11. Harris teaches that “Example 1 shows preparation of a degradable PEG hydrogel having a hydrolytically unstable ester linkage . . . [with] 8-arm PEG . . . [resulting in] hydrogels with a low swelling degree” (Harris ¶¶ 67, 68). 12. Shalaby teaches hydrogel-forming, self-solvating, absorbable polyester copolymers capable of selective, segmental association into Appeal 2013-010631 Application 12/485,192 10 compliant hydrogels upon contacting an aqueous environment. . . . The invention also discloses methods of using the polyester copolymers of the invention in humans for . . . therapeutic treatment of diseases such as cancer and infection of the . . . eye. (Shalaby, col. 1, ll. 10–24). 13. Shalaby teaches that the “copolymer comprises a base component, designated ‘Component A’ herein. . . . Component A optionally comprises carboxylic endgroups” that “facilitate[] ionically binding a biologically active agent or drug to Component A, such that, drug release can be modulated. The biologically active agent or drug is preferably present on Component A in an insoluble form, such as, (I) a microparticulate dispersion” (Shalaby, col. 7, ll. 5–33). 14. Example XXV of Shalaby teaches “[p]reparation and Evaluation of Intravitreal Formulation of Ganciclovir,” wherein “[g]ancyclovir sodium . . . is mixed with a mixture of gel-formers . . . . [T]he formulation was easily administered intravitreally into the rabbit eye” (Shalaby, col. 31, ll. 24–41). 15. Shalaby teaches drugs including cyclosporin (Shalaby, col. 14, l. 20). Appeal 2013-010631 Application 12/485,192 11 Principles of Law “The combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.” KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007). “If a person of ordinary skill can implement a predictable variation, § 103 likely bars its patentability.” Id. at 417. Analysis Harris teaches a synthetic, biocompatible polymeric hydrogel for delivering a therapeutic drug comprising a first linked precursor (i.e., PEG with nucleophilic functional groups, such as alcohol) covalently linked to a second synthetic precursor (i.e., PEG with electrophilic functional groups, such as carboxyl) to form a biocompatible hydrogel (FF 5–6), wherein before crosslinking, the first precursor and/or the second precursor comprise a water-degradable group (i.e., ester), wherein the hydrogel is water- degradable (FF 7–8). Harris teaches that therapeutic agents for the treatment of disease, with a specific example given of taxol formulated in direct contact with a hydrogel (FF 9–10). Harris teaches “hydrogels with a low swelling degree” (FF 11). Harris provides motivation to vary the number of PEGs and adjust the hydrolysis rate, so as to achieve a low-swelling gel (FF 9), rendering the amount of swelling a results-optimizable variable. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456 (CCPA 1955). Appeal 2013-010631 Application 12/485,192 12 With regard to claims 34 and 35, Harris teaches polyethylene glycol repeats composed of nucleophilic functional groups and electrophilic functional groups that react to covalent crosslink the precursors (FF 6). With regard to claim 37, Harris teaches the drug taxol and Shalaby teaches gancyclovir (FF 10, 14). With regard to claim 40, Harris teaches ester as a water-degradable group (FF 9, 11). With regard to claim 41, Harris teaches “a half life of about 4 days” (FF 9), a value falling within the range of claim 41. With regard to claim 44, Harris teaches taxol, a hydrophobic drug (FF 10). Shalaby teaches hydrogels, to include with a therapeutic agent free of encapsulating material and being in direct contact with the hydrogel (FF 12, 14). Shalaby teaches the use of microparticulates forms of the drug (Shalaby 13). With regard to claims 45 and 46, Shalaby teaches the drug cyclosporin (FF 15). Applying the KSR standard of obviousness to the findings of fact, we conclude that the person of ordinary skill reasonably would have found it obvious to use the hydrogel of Harris to deliver an ophthalmic drug in a particulate form free of encapsulating materials and being in particulate form and in direct contact with the hydrogel, as taught by Shalaby because Shalaby teaches that the microparticulate form is a known equivalent that allows the modulation of drug release (FF 13), permitting further control of drug delivery as desired by Harris (FF 6). Such a combination is merely a Appeal 2013-010631 Application 12/485,192 13 “predictable use of prior art elements according to their established functions.” KSR, 550 U.S. at 417. Conclusion of Law The combination of Harris and Shalaby renders claims 33–35, 37, 40, 41, 44–46, and 49 obvious. 35 U.S.C. § 103(a) over Harris, Shalaby, and Nagaoka The issue is: Does the combination of Harris, Shalaby and Nagaoka render claim 36 obvious? Findings of Fact 16. Nagaoka teaches a “copolymer . . . used in medical applications as a so-called hydrogel in a hydrous state” (Nagaoka, col. 4, ll. 43–45). 17. Example 1 of Nagaoka teaches that “methoxypolyethylene glycol methacrylate . . . was dissolved in . . . methyl methacrylate, then 30 mg. of 2,2’-azobis-(2,4-dimethylvaleronitrile) was added as a radical initiator. The stock solution of polymerization thus prepared was poured in a nitrogen atmosphere” (Nagaoka, col. 5, ll. 27–34). 18. Nagaoka teaches that photo-initiated graft copolymerization is more preferable in which a photosensitive group is introduced in the polymer of (B) to allow photolysis to take place to produce a radical and with this radical the monomer (A) is grafted to the polymer of (B). Because, it is possible to define the quantity, structure and position of active groups and to obtain a molecular-designed, high degree of graft of a graft copolymer as compared with the foregoing graft copolymerization based on chain transfer method. (Nagaoka, col. 3, l. 61 to col. 4, l. 2). Appeal 2013-010631 Application 12/485,192 14 Analysis Harris and Shalaby teach the limitations of claim 33 as discussed above. Nagaoka teaches covalent bond formation in a hydrogel by free radical polymerization of functional groups of the precursors (FF 16–18). Applying the KSR standard of obviousness to the findings of fact, we conclude that the person of ordinary skill reasonably would have found it obvious to modify Harris and Shalaby to form hydrogels by way of free radical polymerization of functional groups of the precursors, as taught by Nagaoka because Nagaoka teaches that the radical “photo-initiated” polymerization makes it possible “to define the quantity, structure and position of active groups and to obtain a molecular-designed, high degree of graft of a graft copolymer” (FF 18) compared to other methods. Such a combination is merely a “predictable use of prior art elements according to their established functions.” KSR, 550 U.S. at 417. Conclusion of Law The combination of Harris, Shalaby and Nagaoka renders claim 36 obvious. 35 U.S.C. § 103(a) over Harris, Shalaby, Jain, and Al-Aswad The issue is: Does the combination of Harris, Shalaby, Jain, and Al- Aswad render claims 43 and 45–48 obvious? Findings of Fact 19. Shalaby teaches that “the copolymers of the invention can . . . facilitate the controlled-release of a biologically active agent/drug for . . . Appeal 2013-010631 Application 12/485,192 15 therapeutic treatment of cancer and diseases such as infection of the . . . eye” (Shalaby, col. 8, ll. 11–20). 20. Jain teaches that blocking the action of VEGF appears to be a promising antiangiogenic approach to treating multiple types of solid tumor. Such inhibition can be achieved by direct or indirect targeting of the ligand (VEGF) at the mRNA or protein level . . . . Of interest, aptamer (pegaptanib sodium; Macugen®, Eyetech Pharmaceuticals, Inc., New York, NY) . . . that target VEGF, are FDA-approved for patients with age- related macular degeneration. . . . VEGF blockade by bevacizumab has yielded improved OS [primary endpoint] or PFS [progression-free survival] in cancer patients in four phase III trials when combined with standard chemotherapy. (Jain 25, col. 2). 21. Al-Aswad teaches that: Anterior segment neovascularization can lead to neovascular glaucoma. . . . Early diagnosis and immediate treatment with panretinal laser photocoagulation often leads to regression and neovascularization and lowering of the intraocular pressure . . . . Anterior segment neovascularization results from several ocular and systemic diseases that predispose patients to retinal hypoxia and ischemia with subsequent release of angiogenesis factors such as VEGF . . . . The best known anti-angiogenic agents of this class are the VEGF inhibitors such a bevacizumab. (Al-Aswad 1). Analysis Harris and Shalaby teach the limitations of claim 33 as discussed above. Appeal 2013-010631 Application 12/485,192 16 Jain teaches that anti-VEGF drugs both pegaptinib (also additionally FDA approved for treatment of age-related macular degeneration), as well as bevacizumab (FF 20). Al-Aswad teaches anti-VEGF therapy, e.g., bevacizumab, for treatment of treatment of neovascular glaucoma and lowering of the intraocular pressure (FF 21). Applying the KSR standard of obviousness to the findings of fact, we conclude that the person of ordinary skill reasonably would have found it obvious to use the hydrogel composition of Harris to deliver an ophthalmic drug in a particulate form free of encapsulating materials and being in direct contact with the hydrogel, as taught by Shalaby, and to specifically employ as opthalmic drugs the anti-VEGF drugs pegaptinib and bevacuzumab, for treatment of age-related macular degeneration, glaucoma and lowering of the intraocular pressure, as additionally taught by Jain and Al-Aswad because Harris and Shalaby teach improved treatment of the eye using therapeutic agents in the disclosed hydrogel compositions (FF 8, 12). Such a combination is merely a “predictable use of prior art elements according to their established functions.” KSR, 550 U.S. at 417. Conclusion of Law The combination of Harris, Shalaby, Jain, and Al-Aswad renders claims 43 and 45–48 obvious. SUMMARY In summary, we reverse the rejection under 35 U.S.C. § 112, first paragraph for lacking descriptive support in the Specification. We reverse the Examiner’s anticipation and obviousness rejections under 35 U.S.C. § 102(b) and 35 U.S.C. § 103(a). Appeal 2013-010631 Application 12/485,192 17 We enter the following New Grounds of Rejection: Claims 33–35, 37, 40, 41, 44–46, and 49 are rejected under 35 U.S.C. § 103(a) over Harris and Shalaby. Claim 36 is rejected under 35 U.S.C. § 103(a) over Harris, Shalaby and Nagaoka. Claims 43 and 45–48 are rejected under 35 U.S.C. § 103(a) over Harris, Shalaby, Jain, and Al-Aswad. This decision contains new grounds of rejection pursuant to 37 C.F.R. § 41.50(b) (effective September 13, 2004, 69 Fed. Reg. 49960 (August 12, 2004), 1286 Off. Gaz. Pat. Office 21 (September 7, 2004)). 37 C.F.R. § 41.50(b) provides “[a] new ground of rejection pursuant to this paragraph shall not be considered final for judicial review. 37 C.F.R. § 41.50(b) also provides that the appellant, WITHIN TWO MONTHS FROM THE DATE OF THE DECISION, must exercise one of the following two options with respect to the new ground of rejection to avoid termination of the appeal as to the rejected claims: (1) Reopen prosecution. Submit an appropriate amendment of the claims so rejected or new evidence relating to the claims so rejected, or both, and have the matter reconsidered by the examiner, in which event the proceeding will be remanded to the examiner . . . (2) Request rehearing. Request that the proceeding be reheard under § 41.52 by the Board upon the same record. REVERSED, 37 C.F.R. § 41.50(b)