DETAILED ACTION
Status of Application
The response filed 03/25/2026 has been received, entered and carefully considered. The response affects the instant application accordingly:
Claims 45-47, 49-50, 57-58, 65, 67-69 have been amended.
Claim 56, 66 has been cancelled.
Claim 70-71 has been added.
Claims 45-52, 54-55, 57-58, 60, 64-65, 67-71 are pending in the case.
Claims 45-52, 54-55, 57-58, 60, 64-65, 67-71 are present for examination.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
All grounds not addressed in the action are withdrawn as a result of amendment.
New grounds of rejection are set forth in the current office action as a result of amendment.
New Grounds of Rejection
Due to the amendment of the claims the new grounds of rejection are applied:
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph 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 the first paragraph of pre-AIA 35 U.S.C. 112:
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 45-52, 54-55, 57-58, 60, 64-65, 67-68, 40-71 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 certain compounds of the instantly claimed Formula Id such as
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and
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, it does not reasonably provide enablement for all the compounds embraced by the instant claimed formula; particularly as the formula recites R1 to be a heteroaryl and for R9 to be an alkyl substituted with one or more hydroxyls (-OH) or heterocyclyl. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
The factors to be considered in determining whether a disclosure meets the enablement requirements of 35 U.S.C. 112, first paragraph, have been described in In re Wands, 858 F.2d 731, 8 USPQ2d 1400 (Fed. Cir., 1988). The court in Wands states, “Enablement is not precluded by the necessity for some experimentation, such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is ‘undue’, not ‘experimentation’” (Wands, 8 USPQ2sd 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. “Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations” (Wands, 8 USPQ2d 1404). Among these factors are: (1) the nature of the invention; (2) the breadth of the claims; (3) the state of the prior art; (4) the predictability or unpredictability of the art; (5) the relative skill of those in the art; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary.
While all of these factors are considered, a sufficient amount for a prima facie case is discussed below.
(1) The nature of the invention and (2) the breadth of the claims:
The claims are drawn to the compound of formula (Id) and are useful for the recited treatment. The instant claimed formula recites R1 to be a heteroaryl and for R9 to be an alkyl substituted with one or more hydroxyls (-OH) or heterocyclyl; the specification defines the term “heteroaryl” to be 3-18 membered aromatic ring radical with 2-17 carbon atoms and 1-6 heteroatoms selected from N,O, or S; and defines the term “heterocyclyl” to be a stable 3-18 membered non-aromatic ring radical with 2-12 carbon atoms and 1-6 heteroatoms that are N, O, or S. Thus, the claims taken together with the specification imply that all the compounds embraced by the formula can be made and be used.
(3) The state of the prior art and (4) the predictability or unpredictability of the art:
The instant claims recited for R1 to be a heteroaryl and the term “heteroaryl” is defined to be 3-18 membered aromatic ring radical with 2-17 carbon atoms and 1-6 heteroatoms selected from N,O, S. The state of the art as seen by Ashenhurst addresses that to be aromatic the ring must be cyclic, conjugated all the way around the ring, and be flat (first page). However several rings like a three membered rings, eight membered ring, and ring with a pi electrons in multiples of 4 (like 1,4-Dioxin
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, thiepine
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, and 1,4 diazapentalene
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) are not aromatic. Eight membered rings are not flat which is a requirement to be aromatic (are also generally a ring with a pi electrons in multiples of 4); three membered rings like oxirene, 1H-azirene, and thiepine are antiaromatic and never observed; rings with a pi electrons in multiples of 4 are antiaromatic (sections 3-6 and 8). Wherein the breath of the compounds claimed cannot be made and/or used.
The claims also recite for R9 to be an alkyl substituted with one or more hydroxyls (-OH) or heterocyclyl; the specification defines the term “heterocyclyl” to be a stable 3-18 membered non-aromatic ring radical with 2-12 carbon atoms and 1-6 heteroatoms that are N, O, or S. Wherein the compounds embraced are deemed to have the utility to treat a dermal or ophthalmic condition as the compounds must have a utility.
The state of the art as shown by Danziger et al. addresses that many aspects and modalities are involved in the pharmaceutical art, which as a result makes that art highly unpredictable. Pharmacological activity in general is a very unpredictable area. Note that in cases, involving physiological activity such as the instant case, “the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved”. Se In re Fisher, 427 F.2d 833,166 USPQ 18, 24 (CCPA 1970). The article while directed to automated drug design, specifically addresses the issue of steric hindrance which essentially means that the shape, design, including the kinds and amount of substituents greatly affect the ability and efficacy of a drug to bind to the desired receptor (as the compound must bind to the receptor such as the retinal receptors and to address ocular surface disorders like dry eye) and function appropriately (a lock and key interaction).
(5) The relative skill of those in the art:
The relative skill of those in the art is high, typically an M.D. or a PhD. in medicine like dermatology or ophthalmology.
(6) The amount of direction or guidance presented and (7) the presence or absence of working examples:
The specification has provided guidance for making certain compounds and for certain compounds to have the described utility of addressing dermatologic or ocular surface disorders like dry eye.
However, the specification does not provide guidance to making all the compounds embraced by the breath claimed as a number of heteroaryl rings claimed as addressed above, cannot be made as recited wherein it cannot be made or used for the recited utility.
It also embraces compounds which as addressed by Danziger above, has the issue of steric hindrance to bind to the desired site/receptor in the dermis or the eye to provide the therapeutic effect/utility where compounds that are to certain configurations as exemplified like
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and
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and
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can be made and provide a binding and therapeutic effect, but the claims are written also embrace compounds like
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and
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that have a steric hinderance to be able to bind to the desired site/receptor to have the disclosed utility and the working examples has a limited a specific configuration wherein that specific configuration or a similar limited configuration would have to be present to have a reasonable expectation of success; as it is unlike that all the compounds in the claimed formula are effective for the breath of utility disclosed to the various dermatological and ocular diseases disclosed/claimed and the specification does not provide guidance and support to demonstrate that all the compounds of the claimed formula are capable for the disclosed utility the treatment for the breath of diseases recited/disclosed as a number of compounds cannot be made or have steric hinderance to bind to the desired area/receptor site..
Considering the state of the art as discussed by the references above, particularly with regards to the scope of enablement to the compounds to be made within the formula and the issue of steric hindrance with regards to the compound configuration and substituent for binding for therapeutic activity and the high unpredictability in the art as evidenced therein, and the lack of guidance provided in the specification, one of ordinary skill in the art would be burdened with undue experimentation to practice the invention commensurate in the scope of the claims.
(8) The quantity of experimentation necessary:
Considering the state of the art as discussed by the references above, particularly with regards to make and use the compounds of the recited formula and the high unpredictability in the art as evidenced therein, and the lack of guidance provided in the specification, one of ordinary skill in the art would be burdened with undue experimentation to practice the invention commensurate in the scope of the claims.
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, 54-55, 57-58, 60, 64-65, 67-71 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).
Burnier et al. does not teach the specific ester prodrugs of the instant claimed formula such as 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].
Rautio et al. teaches that prodrugs are an established tool to improve properties of pharmacological active agents (Abstract) and that a prodrug can consist of two pharmacological actives that are coupled together in a single molecule where each drug acta as a promoiety for the other (codrugs) 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). Known esters forms are seen in table 1 and 5.
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 like methyl, dimethyl, ethyl, propyl - 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 modify the carboxylic acid on the lifitegrast compound
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to an ester prodrug in combination with lipoic acid as a mutual prodrug (codrug) as suggested by Rautio et al. and Barber et al. and Koufaki and Das et al. and produce the instant invention. As Rautio addresses that prodrugs such as codrugs 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; 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/codrug as prodrugs are taught with the known linkage with a reasonable expectation of success.
Response to Arguments:
Applicant's arguments are centered on the assertion that the instant claimed compounds are stable in aqueous buffer but are readily hydrolyzed in certain biological environments citing Table 2 and Table 3, the assertion that Burnier’s compound has a carboxylic group -COOH but the instant compound formula is to the specific ester or anhydride and that Burnier is silent on any compound having such a stability provide or recognizing any reason why such a stability profile would be desirable for the compound, and the assertion that the Office failed to provide any reason why the skilled artisan would modify the compound with the specific R group with a reasonable expectation of success.
The arguments have been fully considered but are not persuasive. Applicant’s assertion that Table 2 and 3 demonstrate that the compounds are stable in aqueous buffer and readily hydrolyzed in certain biologic environments is not persuasive as Rautio establishes that ester prodrugs often enhance lipophilicity (hydrophobic, more stable in water) and thus passive membrane permeability of water soluble drugs by masking charged groups like carboxylic acids and that the prodrugs are activated by enzymatic hydrolysis wherein these properties are not unexpected but rather expected.
As for the assertion that Burnier’s compound is to a carboxylic acid group while the instant compounds is to an ester or anhydride and that it is silent on a desirable stability profile, this is not persuasive. Contrary to Applicant’s assertion Burnier does teach prodrugs such as ester prodrugs for the compounds taught wherein there is an explicit teaching for the form. Additionally Applicant's arguments are against Burnier individually, and one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). As Burnier teaches the compound to have prodrug forms such as ester forms, and Rautio establishes that ester prodrugs often enhance lipophilicity (hydrophobic, more stable in water) and thus passive membrane permeability of water soluble drugs by masking charged groups like carboxylic acids wherein the improved stability and properties are known with a reasonable expectation of success.
As for the assertion that there is no rational for the specific R group of the instant formula, this is not persuasive as seen by the case of obviousness above; as it is prima facie obvious to form a mutual prodrug/codrug with two actives useful for the same purpose for their additive effect with known linkage with a reasonable expectation of success.
Accordingly, the rejection stands.
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, 54-55, 57-58, 60, 64-65, 67-71 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.
Response to Arguments:
Applicant's arguments are centered on the assertion that none of the copending claims read on the instant claimed compounds. This is fully considered but not persuasive. The copending claims embrace compounds that fall within the instant claims, such as when Lz is -O(C=O)(OCR8C9)z- with z=1 and R8=R9=H with R=substituted alkyl with substituent as -OH; and also has claims to
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and
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.
Accordingly, the rejection stands.
Claims 45-52, 54-55, 57-58, 60, 64-65, 67-71 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.
Response to Arguments:
Applicant's arguments are centered on the assertion that none of the patented claims read on the instant claimed compounds. This is fully considered but not persuasive. The patented claims recite compounds falling within the instant claimed formula as R9 has optionally substituted alkyls and the patented disclosure recites that optionally substituted groups include hydroxyls, and the patented claims also recite compounds like
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. Where
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and patented compounds like
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.
Accordingly, the rejection stands.
Conclusion
Claims 45-52, 54-55, 57-58, 60, 64-65, 67-71 are rejected.
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 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
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