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 .
DETAILED ACTION
1. This application is a 371 of PCT/CN2022/075714 02/09/2022; FOREIGN APPLICATIONS: CHINA 202110182307.8 02/09/2021.
Claims 1, 9-16, 18-24 are pending.
Response to Restriction Election
2. Applicant’s election of group I and the species, compound 4,
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in the reply filed on January 5, 2026 was previously acknowledged. The election was made without traverse (MPEP § 818.03(a)). According to applicants’ representative claims 1, 9-15, 18, 20 and 24 read on the elected species. Claim 11 does not read on the elected species since in claim 11, the W-Y-Z-U-T-V requires Z be R4 where R4 is H, however in the elected species R4 must be the M-B construct with CO-alkyl-cyano group. As detailed in the following rejections, the generic claim encompassing the elected species was not found patentable. The search and examination was continued until prior art was found that anticipated or rendered obvious a non-elected species that falls within the scope of the generic Markush claim reading on the elected species. As per MPEP 803.02 II. C. “[T]he examiner must continue to search the species of the claim unless the claim has been found to be unpatentable over prior art.” The examiner “need not continue to search the claim if the claim is rejected over prior art”. [ibid. D.] Therefore, the search and examination is restricted to the claims reading on the elected species, and claims not reading on the elected species are held withdrawn. Accordingly, claim 11, which does not read on the elected species is withdrawn.
The rejection of claims 1, 9-10, 12-13, 18, 20 and 24 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement is maintained for new matter is maintained. Applicant’s representative’s arguments submitted on May 26, 2026 and been fully considered but are unpersuasive. The rejection of claims 1, 9-10, 12-13, 18, 20 and 24 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement for various functional limitations with regard to clogP is withdrawn based upon the amendments. The rejection of claims 1, 9-10, 12-15, 18, 20 and 24 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to define G’ is withdrawn based upon the amendments but is maintained for other issues. The rejection of claim 14 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 for random lines in the claim is withdrawn based upon the amendments. The rejection of claim(s) 1, 9-10, 12-13, 18 under 35 U.S.C. 102(a)(1) as being anticipated by Lin is withdrawn based upon the amendments. The rejection of claim 14 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends is withdrawn based upon the amendments. The rejection of claim(s) 1, 10, 20 and 24 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Katritzky is withdrawn based upon the amendments. The rejection of claim(s) 1, 9-10, 12-15, 18, 20 and 24 under 35 U.S.C. 103 as being unpatentable over Bolen WO 2020176859 A1 further in view of Higuchi US 20160015684 A1 is maintained. Applicant’s representative’s arguments submitted on May 26, 2026 and been fully considered but are unpersuasive. According to the arguments on page 26 while Boland discloses topical medications applicant argues there is no motivation to improve transdermal properties. According to the argument on page 27 some compounds with certain groups failed to have improved transdermal delivery. There is a further argument that it would be no “reasonable expectation of understanding the structure activity relationship”. The examiner disagrees as set forth in the rejection Higuchi’s esters have a good balance of molecular weight and lipophilicity, which would deliver improvements in drug delivery without noticeably compromising other properties. These alkyl esters increase ClogP in a predictable manner. With respect to the argument in bold underline on page 28 that “the transdermal property of the inventive compounds is significantly improved relative to the prototype drug”. This is the expected result of masking a highly charged moiety with a lipophilic alkyl ester. There has been no allegation of improvement over the drugs of Bolden or an improvement that is larger than expected from making the alkyl esters of Higuchi.
Claim Rejections - 35 USC § 112 (a)
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.
3. Claims 1, 9-10, 12-13, 18, 20 and 24 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a rejection for new matter. This is a rejection for new matter. Claim 1 has a limitation of R3 as “C5-C20 alkyl”, which was previously C1-C20 alkyl. No range of R3 as C5-C20 alkyl, is disclosed in the specification
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.
4. Claim(s) 1, 9-10, 12-15, 18, 20 and 24 is/are rejected under 35 U.S.C. 103 as being unpatentable over Bolen WO 2020176859 A1 (cited on the IDS) further in view of Higuchi US 20160015684 A1. 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 are summarized as follows:
Determination of the scope and content of the prior art
(MPEP 2141.01)
The table on page 47-55 teaches various prodrugs of tofacitinib, which is Formula I-A of claim 13, the first formula G in claim 9, which encompasses the elected species G unit. These compounds include but are not limited to compounds I-3, I-4, I-5, I-19, I-20, I21, which are compounds of claim 1 wherein in structure IIB Y and T are N, Z and U CR4, one R4 is H another is the last choice where M is NR8, R8 is methyl, B is piperidine, R7 is methyl, R6 is the third selection, W and V are CR4 where R4 is H, where R1/R2 are H or alkyl, L is a bond and R3 is substituted alkyl or alternatively, L is an alkylene and R3 is substituted alkyl.1
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According to page 113 “[00274] Compositions of the present invention may be administered orally, parenterally, enterally, intracistemally, intraperitoneally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir…[00288] Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. ….Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel..” Specific examples in claim 20 are described on page 113 “partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, di sodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.” Surfactants are discussed on page 118, “In some further embodiments, the lipid vehicle contains one or more oils or lipids together with one or more water-insoluble surfactants, optionally together with one or more co-solvents. In some embodiments, the lipid vehicle contains one or more oils or lipids together with one or more water-soluble surfactants, optionally together with one or more cosolvents. In some embodiments, the lipid vehicle contains a mixture of oil/lipid, surfactant and co-solvent. In some embodiments, the lipid vehicle consists essentially of one or more surfactants/ co-surfactants/ co-emulsifiers, and/ or solvents/ co-solvents.” Various specific surfactants and fatty acid esters are listed on pages 118-119.
Higuchi discusses an ester prodrug approach to improving some hydroxytetralins. The strategy is discussed on page 2 “[0018] Prodrug or a bioreversible derivatization approach to improve oral bioavailability of drugs prone to first pass inactivation has been reported.” By making prodrugs, “[O]rally bioavailable composition and dosage form that enables safe and efficacious levels of hydroxy N-substituted-2-aminotetralin.” [0022] To this end Higuchi prepares a number of alkyl esters of the formula on page 3 ”
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wherein R1 is selected from the group of C6-14alkylcarbonyl.”
Examples in the Table on page 27ff. include the 6-13 carbon acids (where R3 is C5-C12 alkyl):
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Additional Examples in the table on page 32 ff include C14 and C16 ester compounds. The first compound in claim 15 has the 7 carbon chain, the 2nd the 5 carbon chain, the 4th compound a 15 carbon chain, the 5th an 11 carbon chain etc.. Additional compounds include branched chain ethyl carpoates similar to the elected species on pages 35 ff. including example A25 on page 37 and Example A 31 on page 39. These alkyl esters increase ClogP in a predictable manner.
Ascertainment of the difference between the prior art and the claims
The prior art differs only in the identity of the ester substituent. Bolen is drawn to acetoxy ester prodrugs terminated in a large triacylglycerol, while the instant claims have the same acetoxy type ester with a C5-C20 carboxylic acid taught by Higuchi.
Finding of prima facie obviousness
Rationale and Motivation
(MPEP 2142-2143)
It would have been obvious to one of ordinary skill in the art at the time the claimed invention was made to incorporate a different ester in the acetoxy prodrugs of the Bolen. There is a strong motivation in drug design to reduce the molecular weight of a drug in order to increase oral bioavailability. Poor absorption is more likely with larger compounds. Membrane permeability goes down for compounds with a high molecular weight. High molecular weight compounds often have low water solubility, limiting their ability to dissolve in the gastrointestinal tract and introduce trouble with formulations. Larger, more complex structures have a higher risk of binding to unintended proteins or receptors, causing unwanted side effects leading to increased toxicity. The immune system may also recognize large molecules triggering an unwanted immune response. Higuchi’s esters have a good balance of molecular weight and lipophilicity, which would deliver improvements in drug delivery without noticeably compromising other properties. The terminal group on the Bolen prodrugs is also quite large and would be less atom economical to produce as compared to the ester of Higuchi.
A reference is good not only for what it teaches by direct anticipation but also for what one of ordinary skill in the art might reasonably infer from the teachings. (In re Opprecht 12 USPQ 2d 1235, 1236 (Fed Cir. 1989); In re Bode 193 USPQ 12 (CCPA) 1976). In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103. From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Conclusion
5. THIS ACTION IS MADE FINAL. 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 DAVID K O'DELL whose telephone number is (571)272-9071. The examiner can normally be reached on Monday - Friday 9:30 - 7:00 PM.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Clinton Brooks can be reached on 571-270-7682. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/DAVID K O'DELL/Primary Examiner, Art Unit 1621
1 The claims are written in a manner that anything over a 5 carbon alkyl chain can be generated a number of ways, relying on L as a bond and listing the number of carbons in the R3 alkyl or by the formula (carbons in L + carbons in R3). For example where L is a bond and R3 is C8 alkyl or alternatively, L is an alkylene varying from 1-3 carbons and R3 is substituted alkyl varying from 5-7 carbons such that they add up to C8 alkyl chain. Since a substituent is alkyl, other ways the language could generate this same chain would be to consider the substituent but a further member of the chain, i.e. a 9 carbon chain generated variously as described above where the substituents are alkyl.
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