DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
This is a Final Office Action.
Claims 1-15 and 17-25 are pending and under examination.
Claim Objections
The objection to claim 1 because of the formula (I.1) and formula (I.0), is withdrawn based on the amendments.
The objection to claim 14 because of the “>” is withdrawn based on the amendments.
The objection to claims 9, 10, and 12 because of the phrase “selected from the group consisting” is withdrawn based on the amendments.
Claim 1 is objected to because of the following informalities: the ">" in the definition of R4 on page 5 should be removed or amended to what is intended. Appropriate correction is required.
Claims 1 and 14 have been amended but there is still another instance of the “>” in the definition of R4 variable. Thus, the objection is maintained over claim 1.
Claims 12-15 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Claim Rejections - 35 USC § 112
The rejection of claim 7 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for the bond or methyl adjacent to the chloro substituent being ambiguous, is withdrawn based on the amendments.
The following is a quotation of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), first paragraph:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 21-24 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for the treatment of diabetic macular edema, dry and wet age-related macular degeneration, geographic atrophy, non-exudative choroidal neovascularization and urticaria, does not reasonably provide enablement for the curing of diabetic macular edema, dry and wet age-related macular degeneration, geographic atrophy, non-exudative choroidal neovascularization and urticaria; or the treatment and curing of NASH or allergies, inflammation and ocular diseases, generally. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The specification on page 12 defines treatment as curative.
The how to use requirement of the enablement statute, when applied to method
claims, refers to operability and how to use the claimed method work. Pursuant to In re
Wands, 858 F.2d 731,737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), one considers the
following factors to determine whether undue experimentation is required: (A) The
breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D)
The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount
of direction provided by the inventor; (G) The existence of working examples; and (H)
The quantity of experimentation needed to make or use the invention based on the
content of the disclosure, some experimentation is not fatal; the issue is whether the
amount of experimentation is "undue"; see In re Vaeck, 20 USPQ2d 1438, 1444.
The pharmaceutical art is unpredictable. The specification does not enable any physician skilled in the art of medicine, to make the invention commensurate in scope with these claims.
As a general rule, enablement must be commensurate with the scope of claim language. MPEP 2164.08 states, “The Federal Circuit has repeatedly held that “the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation’.” In re Wright, 999 F.2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)” (emphasis added). The “make and use the full scope of the invention without undue experimentation” language was repeated in 2005 in Warner-Lambert Co. v. Teva Pharmaceuticals USA Inc., 75 USPQ2d 1865, and Scripps Research Institute v. Nemerson, 78 USPQ2d 1019 asserts: “A lack of enablement for the full scope of a claim, however, is a legitimate rejection.” The principle was explicitly affirmed most recently in Auto. Tech. Int’l, Inc. v. BMW of N. Am., Inc., 501 F.3d 1274, 84 USPQ2d 1108 (Fed. Cir. 2007), Monsanto Co. v. Syngenta Seeds, Inc., 503 F.3d 1352, 84 U.S.P.Q.2d 1705 (Fed. Cir. 2007), and Sitrick v. Dreamworks, LLC, 516 F.3d 993, 85 USPQ2d 1826 (Fed. Cir. 2008). See also In re Cortright, 49 USPQ2d 1464, 1466 and Bristol-Myers Squibb Co. v. Rhone-Poulenc Rorer Inc., 49 USPQ2d 1370.
The main issue here is the lack of any correlation between a platelet activating factor receptor antagonist and the lack of any pharmacological data, the predictability in the art, the state of the pharmacological arts and the breadth of the claims.
There are several biological assays, drawn to 1) the evaluation of the inhibition of PAFR activation, with data on pages 61-62; 2) evaluation of the inverse agonism mode as a prophetic assay; 3) evaluation of the in vivo efficacy in an animal model of laser-induced choroidal neovascularization in rats, which is prophetic; 4) evaluation of binding of compounds to melanin, which is prophetic; 5) evaluation of chemical stability with data on page 64; 6) evaluation of permeability, which is prophetic; 7) evaluation of metabolic stability in human or rate liver microsomes, which is prophetic; 8) evaluation of metabolic stability in human or rate hepatocytes, which is prophetic; 9) evaluation of plasma protein binding, which is prophetic; 10) evaluation of solubility, with data on pages 66-67; and 11) evaluation of pharmacokinetic characteristics in rodents, which is prophetic.
The scope of the claims involves all of the millions of compounds of claim 1 and the hundreds of diseases and/or conditions embraced by claims 21-24.
Thus, the scope of the claims is very broad.
Due to the level of unpredictability in the art, the very limited guidance provided, and the lack of working examples, the applicant has shown lack of enablement. MPEP 2164.01 (a) states, "A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)." That conclusion is clearly justified here.
Claims 21 and 24 have been amended to a method for the therapeutic treatment” but this does not overcome the enablement rejection. Therapeutic treatment also embraces curative, which is not enabled.
Moreover, claim 21 embraces any ocular disease and claim 24 embraces all allergies and inflammatory-related conditions, for which the application is not enabled.
Eye disorders can be defined by the following diseases, but are not limited to: Hordeolum ("stye" or "sty"), Chalazion, Blepharitis, Entropion and trichiasis, Ectropion, Lagophthalmos, Blepharochalasis, Ptosis, Xanthelasma of eyelid, Dermatitis of eyelid due to Demodex species, leishmaniasis, loiasis, onchocerciasis, phthiriasis, herpesviral (herpes simplex) infection, leprosy, molluscum contagiosum, tuberculosis, yaws, zoster, Involvement of eyelid in impetigo, Dacryoadenitis, Epiphora, Dysthyroid exophthalmos, Conjunctivitis, Pterygium, Subconjunctival hemorrhage, Scleritis, Keratitis, Corneal ulcer / Corneal abrasion, Snow blindness / Arc eye, Thygeson's superficial punctate keratopathy, Corneal neovascularization, Fuchs' dystrophy, Keratoconus, Keratoconjunctivitis sicca, Iritis, Uveitis, Cataract, Retinal detachment, Retinoschisis, Hypertensive retinopathy, Diabetic retinopathy, Retinopathy, Retinopathy of prematurity, Age-related macular degeneration, Macular degeneration, Retinitis pigmentosa, Macular edema,Glaucoma, Floaters, Leber's hereditary optic neuropathy, Strabismus, Ophthalmoparesis, Progressive external ophthalmoplegia, Esotropia, Exotropia, Hyperopia (Farsightedness), Myopia, (Nearsightedness), Astigmatism, Anisometropia, Presbyopia, Internal ophthalmoplegia, .Amblyopia (lazy eye), Leber's congenital amaurosis, Scotoma (blind spot), Color blindness, Achromatopsia / Maskun, Nyctalopia (Nightblindness), Blindness, River blindness, Red eye, Argyll Robertson pupil, Keratomycosis, Xerophthalmia and Aniridia.
Not all inflammatory diseases are treated the same. For example, rheumatoid arthritis (RA) is treated with an alpha-TNF inhibitor or JAK inhibitor because NSAIDs are not effective for the treatment of RA. Furthermore, despite intensive efforts, pharmaceutical science has been unable to find a way of getting a compound to be effective for the treatment of ocular diseases, allergies and/or inflammation generally. Under such circumstances, it is proper for the PTO to require evidence that such an unprecedented feat has actually been accomplished, In re Ferens, 163 USPQ 609.
Therefore, the scope of the claims is not enabled and the rejection is maintained.
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, 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. Patentability shall not be negatived by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims under 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of 35 U.S.C. 103(c) and potential 35 U.S.C. 102(e), (f) or (g) prior art under 35 U.S.C. 103(a).
Claims 1-11 and 17-24 (claims 21-24 were mistakenly left off the previous rejection) are rejected under AIA 35 U.S.C. 103(a) as being unpatentable over Weber et al. (US 5532233) in view of and Weber et al. (Medicinal research reviews 9.2 (1989): 181-218).
The present application claims are drawn to compounds of formula (I.0) and methods for treating ocular disease, allergies, inflammatory conditions and diseases, urticaria and NASH. The general formula of claim 1.
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Weber et al. teaches similar compounds as shown below and on page 187.
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The differences between the claimed compounds and the compounds cited above are 1) the bond between the nitrogen in the seven-membered ring and the adjacent carbon, double versus Applicant’s single; 2) the stereochemistry at the same carbon; and 3) the stereochemistry at the amide bond.
The ‘233 patent also teaches the bond between the nitrogen in the seven-membered ring and the adjacent carbon may be single or double, see column 70, formulas Ia and Ib.
The ‘233 patent teaches racemic mixtures of the compounds. Applicants are requested to note that MPEP § 2144.09 teaches that stereoisomers are prima facie obvious. See also In re May, 574 f.2d 1082, 197 USPQ 601 (CCPA 1978).
The ‘233 patent also teaches phenyl and alkylene-heteroaryl groups at R3 or R4, see columns 57-58, compound 104, and columns 51-52, compound 61.
The ‘233 reference teaches the treatment of inflammation and diabetes, see columns 19-20.
Both references teach the same utility as the present application.
Therefore, said claims are rendered obvious.
Applicant traverses by stating, “As noted by the Examiner, the '233 patent describes two structural variants. One skilled in the art would need to find some motivation in the combination of Weber et al. and the '233 patent to modify the compounds of Weber et al. to include a single bond between the nitrogen in the seven membered ring and the adjacent carbon (as shown in compound of formula (Ib) of the '233 patent). The '233 patent contains only a few specific examples for compounds of formula (Tb), and it does not disclose the IC₅₀ value for any one of the compounds containing a single bond in the diazepine moiety. Therefore, one skilled in the art would find no suggestion or motivation in the '233 patent to modify the structure of compound 18 in Weber et al. to remove the additional double bond from the seven membered ring.”
This is not persuasive. The same utility is disclosed in both references and given that there is always a need to enhance the pharmacological effects of a compound (e.g. increased in vivo half-life) without significantly altering its basic chemical structure, or that there is always a need to reduce the time, cost, risk, and statistical imprecision of pharmacokinetic studies (e.g. measure bioavailability or identify metabolites), and that there is only a limited number of ways that this can be done, it would be obvious to pursue a potential solution that has a reasonable expectation of success. See e.g. KSR International Co. v. Teleflex Inc., 1385, 1397; Pfizer, Inc. v. Apotex, Inc., 82 USPQ2d 1321; Alza Corp. v. Mylan Laboratories, Inc., 80 USPQ2d 1001; In re Kubin, 90 USPQ2d 1417; In re O'Farrell, 7 USPQ2d 1673, 1681; In re Eli Lilly & Co., 14 USPQ2d 1741; In re Ball Corp., 18 USPQ2d 1491.
Applicant further states, “In addition, one skilled in the art would recognize that the structural difference formula (Ia) and (Ib) of the '233 patent are substantial. Changing the oxidation state of the C=N unit (unsaturated vs. saturated) does not take into account the delicate dependency of the binding of the entire molecule on the saturation state of the C=N/HC-NH part in the 7- membered ring that significantly impacts the interaction of the various residues with the receptor. The alignment of these interacting residues severely depends on the oxidation state of this very C=N/HC-NH unit, being it made of a Csp2, as within the C=N group, or a Csp3 hybridized, as within the CH-NH group, carbon atom. The former carbon atom arranges its three substituents in a trigonal planar fashion (angles between the substituents: 120 degree) while the latter aligns them spherically (angles between the substituents: 109.28 degree) around it. For example, the various substituents about this unit, particularly the 2-chlorophenyl group, engaging in interaction with the receptor, will be placed at quite different sites depending on the hybridization state of the C=N/HC-NH unit and thus would have to be expected to show differently strong interactions. The Examiner has provided no scientific basis to expect that replacing the double bond with a single bond would results in compounds with comparable binding affinity towards the PAF receptor, let alone any compound with superior properties.”
This is unpersuasive. Obviousness has never required absolute predictability, In re Lamberti, 192 USPQ 278; In re Longi, 225 USPQ 645, 651; In re Moreton, 129 USPQ 288; In re Kronig, USPQ 428; In re Wahl, 145 USPQ 194; In re Mehta, 146 USPQ 284; In re Rinehardt, 189 USPQ 143; In re Merck & Co., Inc. 231 USPQ 375; In re Mochel, 165 USPQ 319. The rejection outlines the equivalency teachings, which renders obvious the compounds noted in the rejection.
Applicant notes, “Applicant is aware of only a few examples of congeneric PAF receptor antagonists having a HC-NH instead of a C=N unit within the diazepine ring. Two comparison pairs were reported in the literature (see Walser, Armin, et al. "Triazolobenzo-and triazolothienodiazepines. as potent antagonists of platelet activating factor." Journal of medicinal chemistry 34.3 (1991): 1209-1221 ("Walser et al.") and US 4,900,729), showing significantly lower binding affinities for the saturated diazepine ring as compared with the corresponding compounds with a C=N unit. (Both references are cited in the information disclosure statement (IDS) filed concurrently with this response. A copy of Walser et al. is included with the IDS.)”
This is not persuasive. Both references are drawn to the same uitility and the ‘233 patent teaches the equivalency of the double bond and the stereoisomers due to the racemic mixture.
Applicant contends, “Lastly, the Examiner states, "The '233 patent teaches racemic mixtures of the compounds." However, the compounds of the '233 patent only contain one chiral center. In contrast, the compounds of the present invention have two chiral centers, leading to four possible stereoisomers: (R,R), (R,S), (S,R) and (S,S). Therefore, even if the combination of Weber et al. in view of the '233 patent describes compounds with a single chiral center, nothing in the combination of references teaches or suggests compounds with two chiral centers.”
This is also not persuasive. The present application has not disclosed that any of the chiral centers provide unexpected results over a racemic mixture, or why one stereoisomer is unexpectedly more effective than another. As noted in the rejection, MPEP § 2144.09 teaches that stereoisomers are prima facie obvious. See also In re May, 574 f.2d 1082, 197 USPQ 601 (CCPA 1978). Furthermore, MPEP states (2144.09): A prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities. "An obviousness rejection based on similarity in chemical structure and function entails the motivation of one skilled in the art to make a claimed compound, in the expectation that compounds similar in structure will have similar properties." In re Payne, 606 F.2d 303, 313, 203 USPQ 245, 254 (CCPA 1979). See In re Papesch, 315 F.2d 381, 137 USPQ 43 (CCPA 1963) (discussed in more detail below) and In re Dillon, 919 F.2d 688, 16 USPQ2d 1897 (Fed. Cir. 1990).
Thus, the rejection is maintained.
Claims 1-11 and 17-25 (claims 21-24 were mistakenly left off the previous rejection) are rejected under AIA 35 U.S.C. 103(a) as being unpatentable over Weber et al. (US 5532233).
The present application claims are drawn to compounds of formula (I.0) and methods for treating ocular disease, allergies, inflammatory conditions and diseases, urticaria and NASH. The general formula of claim 1 and the species shown below is found in claim 25 of the present application.
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The ‘233 patent teaches similar compounds as shown below:
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.
The difference between the claimed compound and the compound cited above is the fused 6-membered cycloalkyl ring versus Applicant’s 6-membered cycloalkyl ring. These compounds are considered homologues are considered equivalent. The MPEP 2144.09 states “Compounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) or homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977).
The ‘233 patent also teaches the following species:
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, see columns 47-48.
The differences between the claimed compounds and the compounds cited above are 1) the bond between the nitrogen in the seven-membered ring and the adjacent carbon, double versus Applicant’s single; 2) the stereochemistry at the same carbon; 3) the stereochemistry at the amide bond and 4) fused 6-membered cycloalkyl ring versus Applicant’s 6-membered cycloalkyl ring.
The ‘233 patent also teaches the bond between the nitrogen in the seven-membered ring and the adjacent carbon may be single or double, see column 70, formulas Ia and Ib.
The ‘233 patent teaches racemic mixtures of the compounds. Applicants are requested to note that MPEP § 2144.09 teaches that stereoisomers are prima facie obvious. See also In re May, 574 f.2d 1082, 197 USPQ 601 (CCPA 1978).
The ‘233 patent also teaches phenyl and alkylene-heteroaryl groups at R3 or R4, see columns 57-58, compound 104, and columns 51-52, compound 61.
The ‘233 reference teaches the treatment of inflammation and diabetes, see columns 19-20.
Both references teach the same utility as the present application.
The previous discussion on homology is equally applicable here.
Thus, said claims are obvious over the ‘233 patent.
Double Patenting
The rejection of claims 1-25 on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-34 of U.S. Patent No.11766443 in view of Weber et al. (US 5532233) and Weber et al. (Medicinal research reviews 9.2 (1989): 181-218), is withdrawn based on the terminal disclaimer submitted.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SUSANNA MOORE whose telephone number is (571)272-9046. The examiner can normally be reached Monday - Friday, 10:00 am to 7:00 pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Murray can be reached on 571-272-9023. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SUSANNA MOORE/Primary Examiner, Art Unit 1624