NON-FINAL REJECTION
This application is a 35 U.S.C. 371 (national stage) application of PCT/US2020/053486, filed Sep. 30, 2020, which claims benefit of priority to provisional application 62/908,954, filed Oct. 1, 2019.
Claims 1-13, 16, 17, and 34-44, as amended, are pending.
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 .
Election/Restrictions
Applicant’s election without traverse of Group I, drawn to compounds of formula (VII), and compound 121 as the species of formula (VII), in the reply filed on Aug. 1, 2025 is acknowledged.
Claims 9-13, 16, 17, and 34-44 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions and/or species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on Aug. 1, 2025.
Claims 1-8 are pending and under examination.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on Mar 30, 2022; Sep. 27, 2022; May 19, 2023; Oct. 12, 2023; May 29, 2024; and May 16, 2025, are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements have been considered by the examiner.
Claim Rejections - 35 USC § 103
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 (i.e., changing from AIA to pre-AIA ) 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.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 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.
Claims 1-8 are rejected under 35 U.S.C. 103 as being unpatentable over Liu et al. (WO2017/136708, cited on the IDS dated Oct. 12, 2023), in view of Meanwell (J. Med. Chem. 61, 5822−5880 (2018), cited on PTO-892).
Liu et al. disclose compounds of formula (E) (paras. [0007], [0017]), having the structural formula,
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with R1-R4 amino acid side chains selected from the following residues (para. [0006]):
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.
R1, R2, R3, and R4, and the peptide backbone to which they are attached, make up the tetrapeptide portion of formula E, termed the "effector domain," as depicted in claim 1:
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Formula E overlaps formula (VII) as recited by claims 1-2, and the compound of claims 3-5, when in formula E, R1 (together with the adjacent carbon and nitrogen) is a proline residue; R2 is mSerBu (CH2-O-t-butyl); R3 is PhG (phenyl); and R4 is mAla (methyl) (paras. [0006]-[0007]), yielding a compound having the structural formula,
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,
which reads on formula (VII) as recited by claims 1-2, wherein A and B are CH; D is -O(CH2)q- and q is 0; R3, R5, and R6 are methyl; R4 is H; R8 is t-butyl; and n, m, and p are 0, or n, m, and p are 1 and R1, R2, and R7 are H; and is identical to the compound of claim 3, except that the "B" phenyl ring (attached to the ether linker) is unsubstituted, rather than substituted by fluorine.
Thus, formula E of Liu et al. significantly overlaps with Formula (VII) as recited by claims 1-2, and differs from claims 3-5 only in that Liu et al. do not disclose that the "B" phenyl ring (attached to the ether linker) can be substituted by fluorine.
However, Liu et al. disclose that R1 or R3 can be PhF (as shown above), i.e., 4-fluorobenzyl. In addition, many variable groups of formula (I) recited by claim 1 of Liu et al. include halogen (e.g., L1, L2, L3, R13, R15, R15', R17, R19, R20, R21, and R22). Thus, Liu et al. explicitly teach and suggest substituting the compounds of formula E with fluoro.
Furthermore, Meanwell discloses that hydrogen and fluorine are well-known bioisosteres, providing many examples. The judicious substitution of a hydrogen atom in aromatic and heteroaromatic rings by a fluorine atom can exert a significant impact on the properties of a molecule that are of beneficial interest in both drug design and development (p. 5832, right col.). "The small size of fluorine coupled with the high C−F bond strength has inspired its extensive application as a bioisosteric replacement for the hydrogen atom, particularly with respect to modulating the metabolism and conformation of a molecule" (p. 5866, left col.).
The compounds recited by claims 4 and 5 are merely the separated enantiomers of the compound of claim 3. As recognized by Aventis Pharma Deutschland GmbH v. Lupin Ltd., 84 USPQ2d 1197, 499 F.3d 1293 (Fed. Cir. 2007), “[o]rdinarily, one expects a concentrated or purified ingredient to retain the same properties it exhibited in a mixture, and for those properties to be amplified when the ingredient is concentrated or purified; isolation of interesting compounds is a mainstay of the chemist's art. If it is known how to perform such an isolation, doing so ‘is likely the product not of innovation but of ordinary skill and common sense.’” 84 USPQ2d at 1204.
While the cited references do not explicitly disclose that the compounds of formula (VII) are inhibitors of macrophage migration inhibitory factor (MIF) nuclease activity or inhibitors of parthanatos mediated cell death, as recited by claims 6-7, a compound's biochemical mechanism of action is an inherent property of the compound, whether or not it was recognized in the prior art.
As recognized by MPEP § 2112.01, where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). "When the PTO shows a sound basis for believing that the products of the applicant and the prior art are the same, the applicant has the burden of showing that they are not." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990).
Finally, it is implicit in the synthetic procedures disclosed by Liu et al. (Example 1, paras. [0011]-[0015]) that a routine final step would involve washing, separating, or purifying the compounds of Formula E in water or ethanol, i.e., a pharmaceutically acceptable carrier, thus forming, however briefly, a pharmaceutical composition as recited by claim 8.
It would have been predictable to one of ordinary skill in the art as of the effective filing date to select 4 "building blocks" from the limited number disclosed by Liu et al. (fifteen for R1 and R3, and ten for R2 and R4) to arrive at the claimed tetrapeptide effector domain, and modify the "B" phenyl group by substituting a hydrogen with a fluorine with a reasonable expectation of success, because the compounds of Liu et al. are not disclosed to have specificity against any particular drug target, or to treat any particular disease, but rather for generating a chemical library comprising thousands of compounds to screen for activity against the entire human proteome using protein chips (paras. [0004]-[0005]). Liu et al. disclose that approximately 45,000 compounds were obtained as part of the rapafucin library (Fig. 1; para. [0019]). Thus, based on the teachings of the reference, and using bioisosteric replacements known in the art, arriving at any of them, or closely similar variations thereon, would have required nothing more than routine experimentation.
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 1-7 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 2 of U.S. Patent No. 11,708,391 in view of Meanwell (J. Med. Chem. 61, 5822−5880 (2018), cited on PTO-892).
Although the claims at issue are not identical, they are not patentably distinct from each other because the examined claims significantly overlap the reference claims.
Reference claim 2 is drawn to compounds of the following structural formula,
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wherein residues 1 to 4 are selected from 25 options, including
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The formula of reference claim 2 reads on formula (VII) as recited by examined claims 1-2, and the compound of claims 3-5, to the extent that n is 0; R1 is phenyl; R2 and R4 are hydrogen; R2' and R3' (phenyl substituents) are methoxy; R5-R8 are methyl, ethyl, propyl, isopropyl, phenyl, OH, NH2, SH, or CN; R9 is methyl; Residue 4 is methyl (Ala); R10 is H; Residue 3 is phenyl (PhG); R11 is methyl; Residue 2 is CH2-O-t-butyl (mSerBu); Residue 1 and the adjacent R12 nitrogen form a pyrrolidine ring (Pro); and R13 and R14 are H, with a double bond in between, yielding a compound having the structural formula,
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which reads on formula (VII) as recited by examined claims 1-2, wherein A and B are CH; D is
-O(CH2)q- and q is 0; R3, R5, and R6 are methyl; R4 is H; R8 is t-butyl; and n, m, and p are 0, or n, m, and p are 1 and R1, R2, and R7 are H; and is identical to the compound of examined claim 3, except that the "B" phenyl ring (attached to the ether linker) is unsubstituted, rather than substituted by fluorine.
Thus, the formula of reference claim 2 significantly overlaps with Formula (VII) of examined claims 1-2, e.g., wherein A and B are CH; D is -O(CH2)q- and q is 0; and n, m, and p are 0, or n, m, and p are 1, and R1, R2, and/or R7 is H, OH, NH2, CN, methyl, ethyl, or propyl.
Reference claim 2 differs from examined claims 3-5 in that R5-R8 do not include halogen; i.e., reference claim 2 does not recite that phenyl ring "B" of examined formula (VII) can be substituted by fluorine or halogen.
However, in the formula of reference claim 2, R5-R8 can be cyano (CN).
Meanwell discloses that fluorine is known to act as a functional mimetic of the nitrile (cyano, CN) moiety (abstract), and provides examples demonstrating a bioisosteric relationship between fluorine and nitrile, which can have similar biochemical profiles (p. 5864, right col.). The electronic properties of a C−F bond allow fluorine to effectively mimic the nitrile functionality in circumstances that often depend on context (p. 5866, left col; p. 5834, left col.).
The compounds of examined claims 4 and 5 are merely the separated enantiomers of the compound of examined claim 3. As recognized by Aventis Pharma Deutschland GmbH v. Lupin Ltd., 84 USPQ2d 1197, 499 F.3d 1293 (Fed. Cir. 2007), “[o]rdinarily, one expects a concentrated or purified ingredient to retain the same properties it exhibited in a mixture, and for those properties to be amplified when the ingredient is concentrated or purified; isolation of interesting compounds is a mainstay of the chemist's art. If it is known how to perform such an isolation, doing so ‘is likely the product not of innovation but of ordinary skill and common sense.’” 84 USPQ2d at 1204.
While reference claim 2 does not explicitly disclose that the compounds are inhibitors of macrophage migration inhibitory factor (MIF) nuclease activity or inhibitors of parthanatos mediated cell death, as recited by examined claims 6-7, a compound's biochemical mechanism of action is an inherent property of the compound, whether or not it was recognized in the prior art.
As recognized by MPEP § 2112.01, where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). "When the PTO shows a sound basis for believing that the products of the applicant and the prior art are the same, the applicant has the burden of showing that they are not." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990).
It would have been predictable to one of ordinary skill in the art as of the effective filing date to select 4 "building blocks" from the limited number (25) recited by examined claim 2, to arrive at the claimed tetrapeptide effector domain, and modify the "B" phenyl group by replacing cyano (CN) with fluorine with a reasonable expectation of success, because the compounds of reference claim 2 are not disclosed to have specificity against any particular drug target, or to treat any particular disease. Thus, using bioisosteric replacements known in the art, arriving at any of the compounds of reference claim 2, or closely similar variations thereon, would have required nothing more than routine experimentation.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SARA E. TOWNSLEY whose telephone number is 571-270-7672. The examiner can normally be reached on Mon-Fri from 9:00 am to 6:00 pm (EST). If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Jeff S. Lundgren, can be reached at 571-272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SARA ELIZABETH TOWNSLEY/Examiner, Art Unit 1629
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