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 .
Priority
The instant application, filed 02/23/2023 is a Continuation of 16766083 , filed 05/21/2020, now abandoned.
16766083 is a National Stage entry of PCT/US2018/065784 , International Filing Date: 12/14/2018
PCT/US2018/065784 Claims Priority from Provisional Application 62599608 , filed 12/15/2017.
Benefit of priority is to December 15, 2017.
Information Disclosure Statement
The Examiner has considered the reference(s) provided in the 1/29/26 Information Disclosure Statement, and provides a signed and dated copy of such herewith.
Claim Status
Claims 1, 6, 7, 12, 16, 20, 21, 45, 63, 64, 77, 91, 108, 115-135 are currently pending and under examination.
Claims 1, 6, 7, 12, 16, 20, 21, 45, 63, 64, 77, 91, 108, 115-126 and 128-135 are rejected.
Claim 127 is objected to.
Claim Interpretation
The term “stapled protein/peptide” is discussed at pages 20+. The examination will be guided by the definition and example at page 20-21:
…. Accordingly, the stapled (cross-linked) polypeptides described herein have improved biological activity relative to a corresponding non-stapled (un-cross-linked) polypeptide.
"Peptide stapling" is a term coined from a synthetic methodology wherein two olefin- containing side-chains (e.g., cross-linkable side chains) present in a polypeptide chain are covalently joined (e.g., "stapled together") using a ring-closing metathesis (RCM) reaction to form a cross-linked ring ….
The term “protein degrader” is not limited to a protein that degrades or destroys a protein for degradation, but includes a protein that binds to/recruits the actually protein degrader to the vicinity of the protein for degradation. At page 11, a protein degrader is:
….the second protein is a degrader protein, such as, e.g., an E3 ubiquitin ligase or a substrate adaptor for an E3 ubiquitin ligase. …
The term “peptide degron” is defined at page 35:
This disclosure features peptide degrons that bind a protein that is the substrate adaptor for an ubiquitin E3 ligase. In some instances, the degrons bind a WD-40 protein that is the substrate adaptor for an ubiquitin E3 ligase. The degron binds to the substrate recognition domain of the Ubiquitin E3 ligase in a shallow groove and is tolerant of elaboration (i.e., conjugation of a stapled peptide sequence) at either the N- or C-terminus. Exemplary substrate adaptors for an ubiquitin E3 ligase include MDM2, …
Specification
Response to Arguments
Applicant’s arguments, see page 10, filed 1/29/26, with respect to the objection to the specification have been fully considered and are persuasive. The objection to the specification has been withdrawn.
Claim Rejections - 35 USC § 112
Response to Arguments
Applicant’s arguments, see pages 10 and 11, filed 1/29/26, with respect to the rejection under 35 USC 112(b) have been fully considered and are persuasive. This rejection has been withdrawn.
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.
Response to Arguments
Applicant's arguments filed 1/29/26 have been fully considered but they are not persuasive.
Applicant asserts that its amendments to claims 21, 45, 64 and 91 render the rejection moot, but does not explain how. The rejection below is amended accordingly to address the amended claims.
Claims 21, 45, 63, 77, 91, 108, 115, 116, 118-126 and 128-135 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.
Each of claims 21, 45 and 91 encompass large to huge genera of species that possess a respectively claimed property:
For claim 21 that the peptide binds a WD40-repeat protein that is a substrate adapter for an E3 ubiquitin ligase, and can have, as to SEQ ID NO:25, which is seven amino acids in length, up to three of amino acid substitutions, one amino acid deletion, or a combination thereof, as long as the one to three amino acid substitutions are not at 4(V) or 5(P) [but apparently one of these could be deleted?], resulting in a large genus of chimeric polypeptides in which the single defined portion, this being small relative to the polypeptide and the peptide that comprises (ii), is highly variable, within said polypeptide genus that has no other defined structural features or specified critical sequences.
Also for claim 45 similar bases apply as to claim 21 - that the modified protein that binds a WD40-repeat protein that is a substrate adapter for an E3 ubiquitin ligase and can have, as to SEQ ID NO:25, which is seven amino acids in length, up to three of amino acid substitutions, one amino acid deletion, or a combination thereof, as long as the one to three amino acid substitutions are not at 4(V) or 5(P) [but apparently one of these could be deleted?], resulting in a large genus of chimeric polypeptides in which the single defined portion, this small, is highly variable, within a said polypeptide genus that has no other defined structural features or specified critical sequences, and
For claim 91 there are insufficient examples of the peptide having a length up to ten that comprises the six amino acids of SEQ ID Nos. 29 or 30 which bind COP1 protein. The nature and properties of other cojoined amino acids reasonably would affect such binding, and applicant has not provided guidance nor structure/function relationships for such peptides up to ten amino acids in length. This is a species/genus situation in which applicant is leaving the possession of the genus to others.
Although applicant has listed known sequences, such as natural degrons, see for example pages 37-40, there is a paucity of meaningful teachings, examples, disclosures regarding linkers relevant to the genus, and structure/function associations to achieve possession of the respective large genera of claims 21, 45 and 91. The limited modified species that are presented are far from representative of these claimed genera, and there are no relevant and substantial teachings as to how to obtain species commensurate with a respective claimed genus rather than a species that does not fall within the respective claim metes and bounds, which may be an unexpected, undesired product as well as resulting in an unfavorable outcome if administered in accordance with any of the claimed methods.
As but one example of the latter, Ackloo et al., J. Med. Chem. 2025, 68, 1092−1112, previously provided, teaches that the WD40 repeat family is one of the largest protein families, so determining specificity for the desired modified peptides with appropriate and not inappropriate affinity and binding represents challenges that are neither addressed nor resolved in the application as filed.
For these reasons claims 21, 45 and 91 are rejected under this section; applicant was not in possession of what is claimed therein at the time of filing.
The other claims listed above, depending from one of claims 21, 45, and 91, also are rejected based on the respective rejection of one of claims 21, 45 and 91, and further as indicated immediately below.
As to each of claims 63, 77, 115 and 116, there is insufficient support and examples for the range of possible diseases and disorders that are encompassed by the claim, including a lack of actual examples demonstrating the desired treating effect that is commensurate with the breadth and diversity of the species of diseases, disorders and chimeric polypeptides. This is particularly the case where there is a lack of relevant examples and/or structure/function and/or other guidance as to the stapled peptide, such as in claim 77 when combined with the specific degron moieties of claim 64, where previously it was stated, this method claim additionally lacking sufficient support (possession) for the range of possible diseases and disorders that are encompassed by the claim, including a lack of actual examples demonstrating the desired treating effect that is commensurate with the breadth and diversity of the species of diseases, disorders …, [and] the latter including disclosure as to how to determine placement of the stapling, and when referring to claim 64 from which it depends, “also suffers from a lack of sufficient support – such as from examples, structure/function associations, and how to determine locations for stapling for making constructs that span across the range of viral, bacterial and animal proteins that are targeted by the ‘protein-targeting stapled peptide.”
As to new claim 122, see basis above for claim 91 as to more limited size as well as basis for claim 21.
As to new claim 123, there is a lack of possession of the subgenus based on insufficient guidance, structure/function, examples, or other relevant information in the application as filed to show possession of the subgenus “wherein the stapled peptide that binds to MDM2 also binds to MDMX.
As to new claims 124 and 125, there is a lack of possession of the subgenus based on insufficient guidance, structure/function, examples, or other relevant information in the application as filed to show possession of the subgenus that allows for up to three amino acid substitutions of SEQ ID Nos. 6 or 134, the examiner also noting that given the open transition comprising the length of the peptide can be longer than these peptides, introducing a great number of possibly interfering amino acid sequences.
As to new claim 126, there is a lack of possession of the subgenus based on insufficient guidance, structure/function, examples, or other relevant information in the application as filed to show possession of the subgenus given the open transition comprising the length of the peptide can be longer than these peptides, introducing a great number of possibly interfering amino acid sequences.
New claims 128-135 are rejected as depending from claim 124, and additionally as to each of claims 128 and 129 for a lack of representative structures for what is claimed, and additionally as to method claim 134, for a lack of examples, structure/function, and other relevant guidance commensurate with the scope of that is claimed.
Claim Rejections - 35 USC § 102
Response to Arguments
Applicant’s arguments, see pages 11-12, filed 1/29/26, and claim amendments, with respect to the rejection(s) of claim(s) under 35 USC 102(a)(1) for Cromm et al. and Richardson et al. have been fully considered and are persuasive. Therefore, these rejections have been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of the claim amendments, see next section, 35 USC 103, and the 35 USC 102(a)(1) rejection applying Uljon to claim 45 is maintained and modified. Please note that applicant in rebutting the rejection of claim 45 applying Uljon stated that the rejection was moot based on claim amendment but did not specify why or how.
Also, for completeness of the record, although applicant states on page 11 of its Remarks “Claim 14 is incorporated into claim 1. Claim 14 is not rejected on this ground,” the language added to claim 14 in the 1/29/26 claim amendments as to the second moiety, this “comprises a stapled peptide that binds to MDM2,” wherein claim 14 in the 7/10/23 claim set stated, “wherein the second moiety comprises a stapled peptide that binds to the protein degrader.” Thus the amendment to claim 1 extends beyond what was claimed in previous claim 14.
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.
Claim(s) 45 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Uljon et al. (2016; Structural basis for substrate selectivity of the E3 ligase COP1. Structure 24: 687-696), cited in 7/10/23 IDS so not provided.
Uljon et al. teach COP1 peptide substrates at Figure 5A, comprising:
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The Trib1 peptide comprises DQIVPEY, which is SEQ ID NO:25 in its entirety, so anticipates claim 45. Trib1 is considered modified from Trib2 based on sequence differences.
Because the Trib2 peptide also meets the binding limitation of claim 45, and considering that the instant specification at page 70 indicates that Tribble proteins have structurally disordered regions, so this limitation would be met by the Trib2 peptide that has mutations in the COP1 binding site.
Accordingly, claim 45 also is anticipated by Uljon.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Response to Arguments
Applicant’s arguments, see pages 12-17, filed 1/29/26, and claim amendments, with respect to the rejection(s) of claim(s) under 35 USC 103 have been fully considered and are persuasive. Therefore, these rejections have been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of the claim amendments, this modifying a previous 35 USC 102(a)(1) reference.
Claim(s) 1, 6, 7, 12, 16, 20, 64 and 117 are rejected under 35 U.S.C. 103 as being unpatentable over in view of Walensky and Bird, J. Med. Chem. 2014, 57, 6275−6288 (“WB”) Cromm et al. (PCT-237; September 21, 2017; Targeted protein degradation: from chemical biology to drug discovery. Cell Chem Biol. 24(9): 1181-1190), cited in the 7/10/23 IDS so not provided herewith, in view of Walensky and Bird, J. Med. Chem. 2014, 57, 6275−6288 (“WB”).
Cromm et al. teach Proteolysis Targeting Chimeras (PROTACs) at page 1182-1187. PROTACs comprise an first moiety that binds to a protein of interest (POI), which is the Protein for Degradation (PD) set forth in the instant claims, and a second moiety that binds to endogenous E3 ligase. The E3 ligase binds to ubiquitin which degrades the POI.
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Therefore, Cromm et al. teach a chimera comprising a first moiety that binds to a first protein for degradation and a second protein that binds to a protein degrader. At page 1184, last paragraph, Cromm et al. teach small molecule PROTACs using the nutlin3a replacing the peptide E3 ligands, wherein the nutlin3a binds to bind a protein that is the substrate adaptor for an ubiquitin E3 ligase that is MDM2.
However, Cromm does not explicitly teach a stapled peptide that binds to MDM2.
The level of skill in the art is high.
WB teaches advantages of stapling peptides, which include conferring α-helical structure, protease resistance, cellular penetrance, and biological activity, Abstract.
Based on the teachings of WB, one of ordinary skill in the art would have been motivated to substitute the small molecule nutlin3a with a stapled peptide that binds to MDM2 in order to improve, at a minimum, biological activity, this including improved cellular penetrance. There would have been a reasonable expectation of success given the WB-taught advantages of stapled peptides.
Accordingly, claim 1 would have been obvious.
Following a similar motivation to improve, by also having the first moiety comprise a stapled peptide, claim 6 would have been obvious.
Because the stapled peptide binds MDM2, it would not comprise a Bcl2 homology domain, and claim 7 would have been obvious.
Because Cromm et al. does teach a chimera comprising a first moiety that is a small molecule (Claim 12), this a basic clearly taught alternative to a stapled peptide such as set forth and claimed in claim 6, claim 12 would have been obvious. These are merely broad classes of molecules known in the art suitable for the same purpose when properly constructed.
As to claim 16, which provide the three most common (perhaps only) arrangements of two peptide-based components in a chimera, Cromm et al., see above figure, suggests, especially given the lysine, arranging the two components claimed such that the first moiety is attached to the N-terminus of the second moiety, rending claim 16 obvious.
Claim 20’s broad treatment is clearly suggested in Cromm et al., see Abstract, Introduction, and Figure 1, rending claim 20 obvious.
Claim 64 part (a) would have been obvious as suggested by the similar structure in Cromm et al., for 4-hydroxy thalidomide, see Fig. 4 and accompanying text, and page 5.
At page 1184, right col., para. 1, Cromm et al. teach that PROTACs comprising a VHL binding domain have been used in live animals (Claim 117).
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, 6, 7, 12, 16, 20, 21, 45, 63, 91, 108, 115-121 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 3, 4, 48, 51 and 80 of copending Application No. 18030433 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the reference application claims begin with a similar very broad claim 1 and then are directed to or include species that anticipate instant claims 1, 6, 7, 12-16, 21, 45, 63, 91, 108 and 117-121, and method claims 20, 63, 77, 115, 116 (see reference application claims 51 and 53 and preceding noted claims). It is the examiner’s understanding that HDM2 and MDM2 are used interchangeably in the art.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Allowable Subject Matter
Claim 127 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
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 JOSEPH FISCHER whose telephone number is (571)270-7925, and whose direct facsimile number is (571)270-8925. The examiner can normally be reached on Monday to Friday, 9:00 AM to 5:00 PM, however noting that the examiner will not normally be working on Monday/Tuesday and on Wednesday-Friday on alternating weeks, but will promptly answer messages upon his return to work.
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/JOSEPH FISCHER/Primary Examiner, Art Unit 1658
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