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 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election 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is restricted to the claims reading on the elected species, and claims not reading on the elected species are held withdrawn. Accordingly, claim 11, which does not read on the elected species is withdrawn.
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. The G groups in the first formula are said to come from “at least by original claims 2-8”. The last two compounds in claim 1,
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are not found in the original claims or specification and are not part of the original disclosure.
Claim 1 also 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. This is also new matter.
4. 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. An objective standard for determining compliance with the written description requirement is, "does the description clearly allow persons of ordinary skill in the art to recognize that he or she invented what is claimed." In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989). Under Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Fed. Cir. 1991), to satisfy the written description requirement, an applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention, and that the invention, in that context, is whatever is now claimed. The test for sufficiency of support in a parent application is whether the disclosure of the application relied upon "reasonably conveys to the artisan that the inventor had possession at that time of the later claimed subject matter." Ralston Purina Co. v. Far-Mar-Co., Inc., 772 F.2d 1570, 1575, 227 USPQ 177, 179 (Fed. Cir. 1985) (quoting In re Kaslow, 707 F.2d 1366, 1375, 217 USPQ 1089, 1096 (Fed. Cir. 1983)). Whenever the issue arises, the fundamental factual inquiry is whether the specification conveys with reasonable clarity to those skilled in the art that, as of the filing date sought, applicant was in possession of the invention as now claimed. See, e.g., Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Fed. Cir. 1991). See M.P.E.P. § 2163.02. In this case, the skilled artisan would not have reasonably concluded at the time of the invention that applicant was in possession of the entire invention as claimed.
Claim 1 is drawn to compounds of Formula describes as a “A prodrug molecule of a pharmaceutical compound G’ characterized in that the hydrophobicity coefficient CLogP of the drug molecule G' is less than 4;”1. They therefore seek to define compounds by particular functional requirements. The specification, however, does not provide any specific correlation between a particular structural property and the claimed function. The description is unclear for a variety of reasons. The identity of G’ is not given and the calculation of cLogP is highly dependent on a number of factors. According to Lowe, Derrick “Watch that Little Letter “c”” In the Pipeline August 22, 2012, Online “https://www.science.org/content/blog-post/watch-little-letter-c”,
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Since it is unclear how the number is calculated, looking at the structure of any hypothetical prophetic compound and deciding if it meets and decide if it meets claims the requirments of G’ is impossible2. Applicants provide no guidance for identifying the compounds that meet the requirements. In light of this claim 1, 9-10, 12-13, 18, 20 and 24 lack written description.
The fact pattern in this case is similar to that in University of Rochester v. G.D. Searle & Co., 68 USPQ2d 1424 (W.D.N.Y. 2003). In Rochester, there were no compounds known to have the required function. The key similarity between the cases, and the one relevant to this ground of rejection, is the fact that no method (other than trial-and-error) is provided for identifying compounds having the desired function. For this reason, the rejection due to lack of written description is proper.
Claim Rejections - 35 USC § 112 (b)
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.
5. Claims 1, 9-10, 12-15, 18, 20 and 24 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. Claim 1 is said to be drawn to “a prodrug molecule of a pharmaceutical compound G’, however G’ is never defined. There is a G group, however it is unclear if G’ and G are the same. The claim also states that the prodrug molecule is of formula (I) which is depicted with three potential G groups, however it also states that formula (I) is the structure of Formula IIB, or IIC, however Formula I was already defined as Formula I. Formula I cannot both be itself and something else at the same time. The claim also has a broad genus limitation together with a narrow genus that falls within the broad range or limitation (in the same claim). In this case there are two compounds at the end of the claim, which lack antecedent basis since the preamble defines the claim as limited to formula (I) or at least prodrugs of Formula G’, which is undefined. The initial genus of formula (I) with the three G group selections, also falls under the broader generic descriptions of Formula IIB and IIC. The last two specific compounds appear to also fall under the genus of Formula I where G is the first selection. The claim is considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
6. Claim 14 is 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. Claim 14 has used a number of lines in the claim body, some of the lines are under the structures others appear to be through parts of structures, others are through nothing. Claim amendments are governed by 37 C.F.R. 1.121 and section (c) (2) explains the use of strikethrough and/or underlining:
When claim text with markings is required. All claims being currently amended in an amendment paper shall be presented in the claim listing, indicate a status of “currently amended,” and be submitted with markings to indicate the changes that have been made relative to the immediate prior version of the claims. The text of any added subject matter must be shown by underlining the added text. The text of any deleted matter must be shown by strike-through except that double brackets placed before and after the deleted characters may be used to show deletion of five or fewer consecutive characters.
The current amendment has random lines, such that it is unclear what is to be deleted and/or added. Since the material appears to be already there, for example on page 9 the first page of claim 14 all the structures are in the previous version of the claim, it would appear that a strikethrough was intended. However it is unclear which portion is meant to be stricken since almost all of the lines do not pass through any structures. There are exceptions, on page 14 where the first line is actually through the compounds in the second row. The next line on page 14 however passes through the cyclopentane in the first and fourth compounds in the third row, but leaves the second and third compounds untouched. Similarly the first and second compounds in the fourth row have a line through the alkyl chains. Other examples exist. It is unclear what the intention is here.
Claim Rejections - 35 USC § 112 (d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
7. Claim 14 is rejected 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. Claim 14 has the following compounds:
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The (4-isopropyl-phenyl)-1-ethyl group in these compounds requires R3 to be a substituted C2 alkyl, which is excluded from the definitions of R3 in claim 1. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
8. Claim(s) 1, 10, 20 and 24 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Katritzky, “A novel synthesis of esters via substitution of the benzotriazolyl group in 1 (benzotriazol-1-yl)alkyl esters with organozinc reagents.” Synthesis 1991 (1), 69-73. Katritzky teaches compound 3c on page 69. This is a compound of claim 1 wherein in structure IIB Z, Y, U and T are CR4, R4 is H, W and V are N, R1/R2 are H or alkyl, L is a bond and R3 is C5 alkyl. A solution in diethyl ether and DMSO is disclosed on page 72 col. 1, during the ”typical procedure” for its preparation meeting claims 20 and 24. Regarding the limitation, “characterized in that the hydrophobicity coefficient CLogP of the drug molecule G’ is less than 4”3, the language is not limiting because the body of claim 1, describes a structurally complete invention and the functional language only refers to properties of that structure. A claim may recite features of a compound functionally, but the patentability of the compound depends upon the claimed structure, not the use or purpose of that structure. Thus, to limit a compound or composition claim, the functional language must result in a structural difference in the claimed compound or composition. This would require a chemical or nuclear change to atoms of the claimed compound or composition. None of the recited language alters the definitions in the formulae nor adds or removes any atoms from the structure, and the structure is unchanged. Since the language does not structurally limit or affect the compound structure and only states an intended use or purpose of the invention, the language is not limiting. Accordingly, the claim terms do not impart any structural change and therefore have no patentable weight since the structure is capable of performing the intended use. See also MPEP § 2112 - MPEP § 2112.02. Functional language is not limiting where a patentee defines a structurally complete invention in the claim body and uses the preamble only to state a functional purpose or intended implementation of the invention. This is grounded in the statutory distinction, between a physical product and activities that constitute a process (which may include a new “use” of a known invention). The recitation of a new intended use for an old product does not make a claim to that old product patentable.
9. Claim(s) 1, 9-10, 12-13, 18 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Lin, Qiyan “Enantioselective synthesis of Janus kinase inhibitor INCB018424 via an organocatalytic aza-Michael reaction.” Organic Letters, 2009, 11(9), 1999-2002 . Lin discloses the second to last compound in claim 1 as compound 28 in Scheme 2 on page 2001. The (S) isomer is disclosed on page S-13 of the supporting info “Base line separation of both enantiomers, (R)-28 and (S)-28), was achieved using a mobile phase of 10% ethanol and 90% hexanes at room temperature.” These are also both compounds of the two membered genus of the last compound in claim 1, i.e. the depicted racemate, which is the second G group of claim 9.
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.
10. 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.4
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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
11. 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 G’ is not defined as discussed below.
2 The office no longer has a program that calculates log P, and as such the examiner has no way to determine which compounds meet this requirement assuming G’ were defined.
3 The identity of G’ is inscrutable as G’ not defined in the claims as discussed above.
4 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.