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
This Application is a continuation of U.S. Application No. 17/192,083, filed on March 4, 2021, which is a continuation of U.S. Application No. 15/852,854, filed on December 22, 2017, now U.S. Patent No. 10,994,015, which in turn claims priority to U.S. Provisional Patent Application Serial No. 62/438,901, filed on December 23, 2016, and U.S. Provisional Patent Application Serial No. 62/563,494, filed on September 26, 2017.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on June 17, 2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Objections – Numbering of Claims
The claims are objected to because the numbering of claims is not in accordance with 37 CFR 1.126. When new claims are presented, they must be numbered consecutively beginning with the number next following the highest numbered claims previously presented (whether entered or not).
The numbering of claims as presented by the Applicant is 1-12, 14, 13, 14, 15, 16, 17, 18 and 19. The claims have been renumbered consecutively as 1-20.
Claim Status – Response to Restriction/ Election Requirement
Claims 1-20 are currently pending.
Applicant’s election, without traverse, of the following species in the reply filed Mar. 5, 2026 is acknowledged:
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The Applicant indicated that claims 1-3, 5, 13, and 13-19 read on the elected species. Renumbered claims 1-3, 5, 12 and 14-20 appear to read on the elected species.
Claims 1-3, 5, 12 and 14-20 and are currently active and subject to examination. Claims 4, 6-11 and 13 are withdrawn.
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.”
Claims 1, 3, 5, and 14-20 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 directed towards a compound having the structure PTM-L-ULM. One of ordinary skill in the art cannot determine the metes and bounds of the claim because it is unclear both how the PTM is attached to L and how the ULM is attached to L. The claim does not describe how the PTM is attached to L. When the ULM is (1), the claim indicates that the attachment point is anywhere in the ULM:
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, but the claim does not actually describe how the ULM is attached to L. This is further confounded by the fact that the valency of the compounds is unclear. For example, the PTM is defined as:
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, but the claim allows R21 and R22 to be H. It is impossible for each R21 and R22 to be H and also have L attached to the PTM.
Claims 3, 5 and 14-20 depend from claim 1 and do not resolve this ambiguity and are therefore also indefinite.
Claim Rejections – 35 USC § 112(a) – Enablement
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 1-3, 5 and 14-20 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
In order to determine compliance with the enablement requirement of 35 U.S.C. 112(a), the Federal Circuit developed a framework of factors in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), referred to as the Wands factors to assess whether any necessary experimentation required by the specification is “reasonable” or is “undue.” Consistent with Amgen Inc. et al. v. Sanofi et al., 598 U.S. 594, 2023 USPQ2d 602 (2023), the Wands factors continue to provide a framework for assessing enablement in a utility application or patent, regardless of technology area. See Guidelines for Assessing Enablement in Utility Applications and Patents in View of the Supreme Court Decision in Amgen Inc. et al. v. Sanofi et al., 89 FR 1563 (January 10, 2024). These factors include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
The Breadth of the Claims
The claimed invention is directed towards a broad genus of PROTACs . Claim 1 is directed towards a compound of the formula PTM-L-ULM, wherein
the ULM is:
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the PTM is:
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L is –(AL)q , wherein:
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This genus encompasses potentially millions of compounds, and does not require any particular PTM, L or ULM, or a specific arrangement of these elements.
The Nature of the Invention and Level of One of Ordinary Skill in the Art
Applicant’s claimed invention is directed towards PROTACS , which are compounds which target a particular enzyme for degradation using a protein targeting moiety (PTM) linked to a ubiquitin ligase binding moiety (ULM). The particular PROTACs claimed are purportedly useful in the treatment of receptor tyrosine kinase (RTK) mediated diseases (Specification, p. 2-3). Those of ordinary skill in the art understand and practice science related to medicinal chemistry, structural biology, oncology, and cellular signaling, to name a few.
The Amount of Guidance and Existence of Working Examples
In the Background of the Invention (p. 1-4), Applicant summarizes the role of PROTACs in degrading RTKs. In the Summary of the Invention (p. 4-8), Applicant describes the bifunctional compounds which function to recruit endogenous RTKs to E3 ubiquitin ligases to be degraded. Applicant describes the claimed PROTACs in general terms and provides methods of degrading target proteins general, and of treating or ameliorating a disease, disorder, or symptom thereof in a patient, without identifying a particular target or condition.
In the Detailed Description of the Invention (p. 13-337), Applicant describes certain embodiments and concepts pertaining to the invention, including a description of the function of PTMs and ULMs, numerous structures of PTMs, ULMs and linkers (L), pharmaceutical compositions comprising the compounds, therapeutic methods, and additional therapeutic agents useful in combination with the claimed compounds.
The Specification has examples of 351 compounds, only some of which fall within the claimed formula of claim 1. Claims 12 and 13 provide the specific examples which fall within the genus of claim 1. These compounds have largely the same structural features, in which the PTM appears to be based on the known RTK inhibitors gefitinib, afatinib or lapatinib, which have the following structures:
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Gefitinib, Crews et al. (WO2013170147A1), Specification, p. 51;
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Afatinib, Id.
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Lapatinib, Id., p. 48.
The linkers are primary PEG based linkers of similar lengths. The ULM is (1) in the majority of the compounds and (2) in just 5 of the compounds.
The Specification shows that these examples vary significantly in their potency. For example, example 66 having the following structure:
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(para. [0650])
had a score of A in Table 2 for EGFR-WT cells and a rank of C or better for three of four mutant EGFR cell types, while example 100, having the following structure:
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(para. [0830]),
had a score of C for EGFR-WT cells and no activity for mutant EGFR.
The State of the Prior Art and the Level of Predictability in the Art
As it is with many biotechnology inventions, the relevant art is multidisciplinary. Applicant’s claimed invention relates to a number of core technologies and scientific concepts including compound design and screening, cell signaling, tyrosine kinase molecular biology, pharmacology and others. Accordingly, one of ordinary skill in the art would have a firm understanding of the inter-relationship between each of the disciplines and the functional and physical limitation of the claimed invention, and is pertinent to determining the level of skill in the art.
Taken as a whole, the relevant art suggests that the Applicant had not reasonably enabled the claimed invention at the time the Application was filed. The literature suggests that even very similar linkers can significantly impact the potency of EGFR PROTACs. For example, Bondeson et al. (Nature Chemical Biology, 11, pages 611–617 (2015)) teaches that PEG linkers with 3-5 oxygen moieties can have varying potency, even when linked to the same PTMs and ULMs in the same way:
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Bondeson, SF3.
Cyrus et al. (ChemMedChem, Volume 5, Issue 7, Jul 2010, Pages 965-1155) teaches that the placement of the linker also impacts the activity of the resulting PROTAC:
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Cyrus, Scheme 1;
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Cyrus, Fig. 3C.
The cited references, along with the Applicant’s own disclosure that would lead one of ordinary skill in the art to doubt that the Applicant has enabled one of ordinary skill in the art to make and use the full scope of the claimed PROTACs for treating RTK mediated diseases.
The broad diversity in the chemical makeup of the PROTACs in the claimed genus compared with the arts suggestion of variability among even related PROTACS suggests that one of ordinary skill in the art would not be able to reasonably predict which PROTACs in the claimed genus would have therapeutic relevance.
The Quantity of Experimentation
Based on the art cited above and the unresolved issues in the relevant art, the amount of non-routine experimentation required would be high. Accordingly, in order to enable the invention as claimed, one of ordinary skill in the art would have to engage in undue experimentation.
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.”
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.
Claim(s) 1-3, 5, 12 and 14-20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Bondeson et al. (Nature Chemical Biology, 11, pages 611–617 (2015)) in view of Crews et al. (WO2013170147A1).
Claim 1 is directed towards a compound of the formula PTM-L-ULM, wherein
the ULM is:
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the PTM is:
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L is –(AL)q .
For example, a compound falling within the genus of claim 1 is:
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(Instant claim 12)
Bondeson teaches a nearly identical compound of the formula PTM-L-ULM:
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Bondeson, SF3.
Bondeson teaches that the ULM is the VHL ligand having the following structure:
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Bondeson, SF1, which is shown to be attached to the linker as follows:
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Bondeson, Fig. 1.
Bondeson therefore suggests a PROTAC with the structure of PTM-L-ULM wherein the PTM is vandetanib, L is a PEG based linker with 3-5 oxygen atoms and the ULM is the VHL ligand. This differs from the claimed PROTAC in that vandetanib is an RTK wherein the R21 fluoro is in a different place than in the instant invention.
One of ordinary skill in the art would have a reasonable expectation of success, however, to substitute a PTM as in the instant invention for vandetanib because similar PROTACs are commonly known in the art.
For example, Crews teaches that the PROTAC can be made with gefinitib as the PTM:
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Crews, Specification, p. 51.
Crews also teaches that the PTM can be afatinib or lapatinib as in the instant invention:
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Id.;
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Id., p. 48.
Claim 12
Therefore, claim 1 was prima facie obvious at the time of filing.
Claims 2-3, 5, and 12 read on the PROTAC of claim 1, wherein the PTM is gefitinib, afatinib, or lapatinib, L is a PEG linker with 3-5 oxygens, and the ULM is the VHL ligand as described in the rejection of claim 1 above. Therefore, claims 2-3, 5 and 12 were prima facie obvious at the time of filing.
Claim 14 is directed towards a pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier or excipient.
While Bondeson does not teach a pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier or excipient, one of ordinary skill in the art would have a reasonable expectation of success to formulate such a pharmaceutical composition because similar pharmaceutical compositions are commonly known in the art.
For example, Crews teaches pharmaceutical compositions comprising PROTAC compounds along with pharmaceutically acceptable carriers or excipients (Crews, Specification, p. 77).
Therefore, claim 14 was prima facie obvious at the time of filing.
Claims 15 and 16 are directed towards the pharmaceutical composition of claim 14, further comprising an additional bioactive agent (claim 15), wherein the additional agent is an anticancer agent (claim 16).
While Bondeson does not teach a pharmaceutical composition comprising an additional bioactive agent, one of ordinary skill in the art would have a reasonable expectation of success to include an additional bioactive agent, particularly an anticancer agent, because similar compositions are commonly known in the art.
For example, Crews teaches that the composition comprising a PROTAC may additionally comprise another anticancer agent (Crews, Specification, p. 6).
Therefore, claims 15-16 were prima facie obvious at the time of filing.
Claims 17-20 are directed towards treating an RTK related disease in a subject, the method comprising administering the compound of claim 1 to the subject a compound of claim 1, wherein the RTK-related disease is squamous-cell carcinoma of the lung, colon cancer, anal cancer, glioblastoma, or epithelial tumor of the head and neck.
While Bondeson does not teach the above method, one of ordinary skill in the art would have a reasonable expectation of success to treat such cancers with the claimed PROTACs because PROTACs are commonly known in the art for the treatment of these cancers.
For example, Crews teaches that PROTACs can treat squamous cell carcinoma, and cancer of the lung, colon, neck and bowel (Crews, Specification, p. 12).
Therefore, claims 17-20 were prima facie obvious at the time of filing.
Given the above teachings, the invention as a whole was prima facie obvious at the time of filing.
Nonstatutory 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.
Claim(s) 1-3, 5, 12 and 14-20 is/are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of U.S. Patent No. 10,730,870 B2 (herein “the ‘870 patent”) in view of Bondeson et al. (Nature Chemical Biology, 11, pages 611–617 (2015)) and Crews et al. (WO2013170147A1).
While the claims at issue are not identical, they are not patentably distinct because the ‘870 patent claims a compound with the structure PTM-L-ULM, wherein the PTM is a kinase inhibitor, specifically an EGFR inhibitor, and the ULM is the VHL ligand. While the ‘870 patent does not specifically claim the EGFR inhibitors as in the instant application, one of ordinary skill in the art would have a reasonable expectation of success to use the PTMs as in the instant application because they are taught by Bondeson and Crews, as shown in the rejection of claims 1-3, 5, 12 and 14-20 under 35 U.S.C. 103 above, incorporated herein by reference. The ‘870 patent also claims pharmaceutical compositions, which additionally comprise an anticancer agent as instantly claimed. While the ‘870 patent does not claim the same method as the instant application, one of ordinary skill in the art would have a reasonable expectation of success to apply the compounds to the claimed method given the teachings of Crews.
Therefore, the claimed invention is rejected on the grounds of obviousness type double patenting over the claims of the ‘870 patent.
Conclusion
No claim is found to be allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to HEATHER DAHLIN whose telephone number is (571)270-0436. The examiner can normally be reached 9-5.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Lundgren can be reached on (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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/HEATHER DAHLIN/Examiner, Art Unit 1629
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