DETAILED ACTION
Status of Application
Claims 45-52, 54-58, 60, 64-69 are pending.
Claims 45-52, 54-58, 60, 64-69 are present for examination at this time.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Information Disclosure Statement
The information disclosure statement filed 05/19/2023 fails to comply with 37 CFR 1.98(a)(2), which requires a legible copy of each cited foreign patent document; each non-patent literature publication or that portion which caused it to be listed; and all other information or that portion which caused it to be listed. It has been placed in the application file, but the information referred to therein has not been considered.
The information disclosure statement filed 05/19/2023 also fails to comply with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609 because a document is not fully legible as it is missing sections. It has been placed in the application file, but the information referred to therein has not been considered as to the merits. Applicant is advised that the date of any re-submission of any item of information contained in this information disclosure statement or the submission of any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the statement, including all certification requirements for statements under 37 CFR 1.97(e). See MPEP § 609.05(a).
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 45-52, 54-58, 60, 64-67 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The claims recite the terms optional substituents and substituted (i.e. “R1 is optionally substituted heteroaryl”, for R2 and R3 and R4 “wherein the alkoxy, alkyl or cycloalkyl is optionally substituted”, “R5a is optionally substituted aryl”, for R “and further optionally substituted, ”, “substituted aryl”), but does not recite what the required substituent or optional substituent is or what it can be. There is not a specific definition for what the phrase would embrace and the claims do not address what the optional substituents are wherein it does not allow one to ascertain the metes and bounds of the claims as written
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 45-52, 55 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Naik et al. (WO 2019/053607).
Rejection:
Naik et al. teaches the compounds
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(see claim 12) which falls within the claimed formula.
All the critical elements are taught by the cited reference and thus the claims are anticipated.
Claims 45-52, 55 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Naik et al. (WO 2019/053607).
Rejection:
Naik et al. teaches the compounds
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(see claim 12) which falls within the claimed formula.
All the critical elements are taught by the cited reference and thus the claims are anticipated.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 45-52, 54-56, 58, 64-65 are rejected under 35 U.S.C. 103 as being unpatentable over Burnier et al. (U.S. Pat. Pub. 2009/0258070) in view of Rautio et al. (Prodrugs: design and clinical applications).
Rejection:
Burnier et al. teaches LFA-1 antagonists including
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(compound 12, also known as lifitegrast and xiidra) which is explicitly taught, exemplified, formulated, and claimed (abstract, [12-13, 272-275], Table 1-3, Example 4 and 6 and 14-15, claims 21-23). The LFA-1 antagonists including compound 12
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is useful for the treatment of inflammatory eye conditions includ8ing age-related macular degeneration, diabetic retinopathy, and dry eye (claims 33, 37, 42, [28, 229, 231], Example 13-15). The compound can also have RE which is hydrogen or lower alkyl off the piperidine in the isoquinoline-like core(claim 5, [84]), the compound including compound 12
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can include additional therapeutic agents [26], and can be in prodrug form [73] citing ester forms and advantages of prodrugs like solubility for this form ([73], see full document specifically areas cited).
Rautio et al. teaches that prodrugs are an established tool to improve properties of pharmacological active agents (Abstract) and describes the most common functional groups amenable to prodrug design include hydroxyl groups into esters, and that esters are the most common drug form used as it is about 49% of all market prodrugs and ester prodrugs are most often used to enhance the lipophilicity and thus the passive membrane permeability by masking charged groups like carboxylic acids and phosphates; as the synthesis of an ester prodrug is often straight forward, and lipophilic prodrugs achieve improved ocular absorption and safety (Table 1, Esters as prodrugs of carboxyl, hydroxyl and thiol functionalities 1st paragraph Page 256, Ophthalmic drug delivery Page 265). These esters forms include pivaloylmethyl esters, bis-pivaloyoxylmethyl esters, bis-isopropyloxycarbonyloxymethyl ester, dipivalic esters, and isopropyl esters (table 1 and 5).
It would have been obvious to one of ordinary skill in the art at the time the claimed invention was made to modify the carboxylic acid on the lifitegrast compound
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to an ester prodrug such as an isopropyl esters (R is alkyl like
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) or pivaloylmethyl ester (heteroalkyl substituted with at least one oxo like
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) as suggested by Rautio et al. and produce the instant invention. As Rautio addresses that prodrugs are an established tool to improve properties of pharmacological active agents and esters prodrugs are the most common drug form used and most often used to enhance the lipophilicity and thus the passive membrane permeability by masking charged groups like carboxylic acids on the drug and improve the ocular absorption of drugs as lipophilic prodrugs achieve improved ocular absorption and safety, it would be prima facie obvious to form its ester prodrug which is the most common type with its known known ester forms like isopropyl esters and pivaloylmethyl esters as a means to improve the lipophilic properties of drug and improve passive permeability and ocular absorption/safety with a reasonable expectation of success.
Claim 57, 66-69 are rejected under 35 U.S.C. 103 as being unpatentable over Burnier et al. (U.S. Pat. Pub. 2009/0258070) in view of Rautio et al. (Prodrugs: designs and clinical applications) as applied to claims 45-52, 54-56, 58, 64-65 above, further in view of Tilley et al. (Identification of N-acyl 4-(3-pyridonyl)phenylalanine derivatives and their orally active prodrug esters as dual acting α4β1 and α4β7 receptor antagonists).
Rejection:
The teachings of Burnier et al. in view of Rautio et al. are addressed above. Burnier et al. in view of Rautio et al. does not teach prodrug to be where R8 is methyl, but does teach esters are the most common prodrug form used are most used to enhance the lipophilicity and passive membrane permeability by masking charged groups like carboxylic acids where the esters forms include pivaloylmethyl esters (heteroalkyl substituted with at least one oxo) and isopropyl esters (i.e. alkyl esters).
Tilley et al. teaches that in the same prodrug area, known ester prodrugs of carboxyl-containing parent compounds include compound 49
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(see Table 2), which exhibits superior bioavailability compared with a number of other ester linked prodrug candidates.
It would have been obvious to one of ordinary skill in the art at the time the claimed invention was made to modify the lifitegrast prodrug ester to include the
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form as suggested by Tilley et al. and produce the claimed invention; as it is prima facie obvious to a known ester prodrug form
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which exhibited good bioavailability with a reasonable expectation of success.
Claim 60 are rejected under 35 U.S.C. 103 as being unpatentable over Burnier et al. (U.S. Pat. Pub. 2009/0258070) in view of Rautio et al. (Prodrugs: design and clinical applications) as applied to claims 45-52, 54-56, 58, 64-65 above, further in view of Barber et al. (Neurodegeneration in diabetic retinopathy: Potential for novel therapies) and Koufaki (Therapeutic applications of lipoic acid: a patent review (2011 – 2014)) and Das et al. (Codrug: An efficient approach for drug optimization).
Rejection:
The teachings of Burnier et al. in view of Rautio et al. are addressed above.
Burnier et al. in view of Rautio et al. does not expressly teach the compound of claim 60 where the ester for R is derived from lipoic acid
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(also known as alpha lipoic acid), but does teach ester prodrug forms for the LFA-1 antagonists like
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that are useful for diabetic retinopathy, and that the drug can be combined with additional therapeutic agents [26].
Barber et al. teaches that treatments for the neurodegeneration in diabetic retinopathy including lipoic acid (abstract, Diabetic retinopathy as a neurodegenerative disease: Retinal apoptosis Page 83, Lipoic acid Page 87-88),
Koufaki teaches that alpha-lipoic acid is known to in conjugated with other drugs (section 2.2 first paragraph) and useful against neurodegeneration as conjugates (section 2.26) and useful for diabetic retinopathy (Expert opinion 4th paragraph).
Das et al. teaches that codrugs (also known as mutual prodrugs) is an approach where various effective drugs can be attached to other drugs directly or via a linkage to improve drug delivery of the active (abstract, Table 1), that lipoic acid is known to be used as a codrug (mutual prodrug), and with two carboxylic acid drugs (i.e. all trans retinoic acid and butyric acid) the linkage is acyloxylalkyl ester (i.e. lower alkyls-simplest alkyl being methyl, Table 2, neurodegenerative disease).
It would have been obvious to one of ordinary skill in the art at the time the claimed invention was made to combine the LFA-1 inhibitor prodrug with lipoic acid as a mutual prodrug (codrug) as suggested by Barber et al. and Koufaki and Das et al. and produce the claimed invention; as Burnier in view of Rautio teaches the prodrug form and combining actives and Barber et al. teaches that lipoic acid is useful for the same purpose (diabetic retinopathy) it is prima facie obvious to combine two actives useful for the same purpose for their additive effect. As Koufaki and Das teaches that lipoic acid is known to be conjugated with other actives and codrug/mutual prodrugs are a known means of delivering to therapeutic actives where when both are carboxylic acids that the linkage can be acyloxyalkyl esters it is prima facie obvious to form the mutual prodrug as prodrugs are taught with the known linkage with a reasonable expectation of success.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 45-52, 54-58, 60, 64-69 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8, 10, 13-14, 21, 25, 59, 61-66 of copending Application No. 18033055 (reference application).
Although the claims at issue are not identical, they are not patentably distinct from each other because the copending claims containing compounds that fall within the instant claims and with the same method or fall within the recited method wherein they are obvious over the instant claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 45-52, 54-58, 60, 64-69 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 10875845.
Although the claims at issue are not identical, they are not patentably distinct from each other because the copending claims containing compounds that fall within the instant claims and with the same method or fall within the recited method wherein they are obvious over the instant claims.
Conclusion
Claims 45-52, 54-58, 60, 64-69 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GIGI GEORGIANA HUANG whose telephone number is (571)272-9073. The examiner can normally be reached Monday-Thursday 9:00-5:00pm.
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/GIGI G HUANG/Primary Examiner, Art Unit 1613