DETAILED ACTION
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 11/17/2023, is a national stage entry of PCT/EP2022/063422, filed 05/18/2022, which claims foreign priority to FR2105217, filed 05/19/2021. Receipt is acknowledged of certified copies of papers required by 37 CFR § 1.55.
Amendments and Claim Status
The amendment filed on 06/30/2026 is acknowledged and entered.
Claims 1, 10, and 13 are amended;
Claim 2 is cancelled;
Claims 1 and 3-15 are pending.
Response to arguments
Applicant’s arguments filed 06/30/2026 with respect to the objection to the specification, drawings, claim objections, and claim rejections under 35 U.S.C. §§ 112(a), 112(b), 102 (a) (1), and 103 have been fully considered.
With respect to the objection to the specification, the amendment to the specification to replace the low-resolution compounds is insufficient to overcome the rejection. The compounds remain warped and grainy, and are of insufficient quality. Accordingly, the objection is hereby maintained.
With respect to the objection to the drawings, the amendment to the drawings filed 06/30/2026 is sufficient to overcome the objection. Accordingly, the objection to the drawings is hereby withdrawn.
With respect to the objection to the claims 2, 3, 5, 6, 8, the cancellation of claim 2 renders the objection against said claim moot. With respect to the remainder of the claims, Applicant alleges that the claims have been amended to include higher resolution images in order to overcome the objection. However, no such amendment to the claims is reflected within the claim set filed on 06/30/2026.. Even the claimed descriptors designate the claims as “(Previously Presented).” The compounds remain low-resolution and grainy, and are of insufficient quality Despite the assertion that amendments have been made to the claims, no such amendments have been filed. Accordingly, the objection is hereby maintained.
With respect to the rejection of claims 1-7, 9, 10, 12-15 under 35 U.S.C. § 112 (a) as failing to comply with the written description requirement, the cancellation of claim 2 renders the rejection against said claims moot. However, Applicant’s arguments have been fully considered but are not persuasive for the reasons set forth below. The arguments made by Applicant are herein addressed as follows.
The following section of the MPEP is relied upon for the response to Applicant’s arguments. According to MPEP § 2163.02, the standard for determining compliance with the written description requirement is as follows,
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, inventor 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)…Possession may be shown in a variety of ways including description of an actual reduction to practice, or by showing that the invention was "ready for patenting" such as by the disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the inventor was in possession of the claimed invention. See, e.g., Pfaff v. Wells Elecs., Inc., 525 U.S. 55, 68, 119 S.Ct. 304, 312, 48 USPQ2d 1641, 1647 (1998); Regents of the Univ. of Cal. v. Eli Lilly, 119 F.3d 1559, 1568, 43 USPQ2d 1398, 1406 (Fed. Cir. 1997); Amgen, Inc. v. Chugai Pharm., 927 F.2d 1200, 1206, 18 USPQ2d 1016, 1021 (Fed. Cir. 1991) (one must define a compound by "whatever characteristics sufficiently distinguish it"
Applicant asserts that the amendment to claim 1 to requiring that L(PXR) be the specific Formula (II) overcomes the rejection on the grounds of written description because it matches what was synthesized and characterized in the instant disclosure.
Applicant’s argument is found to be unpersuasive, because the amendment does not cure the lack of written description of the genus claimed. For instance, narrowing the independent claim with respect to L(PXR) does not provide support for the broad recitations of L(E3 ligase) and linkers still present in the independent claim, as well as the dependent claims.
Applicant argue that written description doesn’t require every species to be exemplified, and that Formula IIIA/IIIB analogs plus disclosed linkers constitute a representative cross-section sufficient to show possession of the claimed genus.
Applicant’s argument is found to be unpersuasive because the few closed narrow species do not structurally correlate to the full functional breadth of the compounds instantly claimed. Although written description does not require actual reduction to practice of every embodiment, the disclosed species must be representative of the full scope of the claimed genus, and must establish a correlation between structure and function across the scope of the claims. For example, the specification discloses only a limited number of CRBN-recruiting thalidomide-analog E3 ligase moiety. Applicant has not identified a disclosure establishing that the species are structurally representative of the full breadth of L(E3) ligase encompassed by the claims. Furthermore, Applicant has not identified a disclosed structure-function correlation extending across the full scope claimed. A few working embodiments does not equate to the large structural diversity covered by the instant claims—only that Applicant possessed those specific species. The specification does not describe the claimed compounds with sufficient specificity to distinguish them from the universe of possible conjugates and substitutions that can be theoretically made.
Applicant argues that variations in X’ and Y represent “minor structural modifications,” and that the written description requirement is satisfied because the specification “clearly allows” a person of ordinary skill to recognize that the inventor invented what is claimed.
This argument is found unpersuasive because, characterizing in an unexemplified substituent as a “minor structural modification” is an assertion unsupported by citation to any specific disclosure. Firstly, Applicant has not identified any embodiment within the specification that discloses X’ as CH2 or Y as a C1-C6 alkyl group. Within the instant specification, X’ is only —C(O)—, and Y is only H. With respect to X’ as C(O), the sp2 hybridized carbon creates a polar, flat, and “locked” confirmation of the ring, which limits conformational flexibility. The inclusion of CH2, a sp3 hybridized carbon, at the position of X’ does not represent a “minor structural modification,” as the structure would be subject to additional flexibility, and lose its polarity at that position, potentially affecting the association of the complex with receptor targets. With respect to Y as H, this results in a polar and basic N-H bond. The inclusion of Y as a C1-C6 alkyl group converts this position to a nonpolar N-C bond which removes the polar and basic nature of the compounds actually possessed. These structural modifications extend beyond that which is actually possessed by Applicant at the time of filing. The Vas-Cath standard cited by applicant requires that the specification itself convey to a skilled artisan that the inventor was in possession of the claimed subject matter (see MPEP § 2163.02). The cited standard does not permit reliance on a skilled artisan’s inference that unexemplified variants would have been obvious extensions of disclosed embodiments. Absent any identification of supporting disclosure, the grounds of rejection is deemed to be valid.
Applicant argues that linker design is a well-established and formulaic discipline in PROTAC chemistry, and that the specification’s disclosure of representative linker structures confirms possession of the linker concept as broadly claimed.
Applicant’s argument is found unpersuasive because applicant’s contention that a skilled artisan would understand how to design or select linkers falling within the claimed ranges, is directed to an “enablement inquiry” under the Wands factors and does not apply to, nor does it satisfy the written description requirement. Knowledge in the art of the general design toolkit does not establish that Applicant possessed the specific, full scope as claimed. Written description requires possession, and not merely feasibility. While the level of skill in the art is relevant, it cannot substitute for written description the demonstrate possession of the claimed compounds. The number of linkers instantly claimed falls well beyond that which was actually possessed by applicant at the time of filing. The written description requirement is satisfied only when the specification reasonably conveys to those skilled in the art that the inventor had possession of the claimed subject matter as of the filing date. General statements of feasibility or references to what could be made by a skilled artisan do not establish possession.
Applicant generally argues that the written description exists to claims 6, 7, 9, 10, and 12 the representative species recited are exemplified within the specification.
Applicant’s argument is not persuasive because the claims continue to be drawn to substituents which are not supported within the specification e.g., linkers, L2, etc. Because the claims continue to be drawn to substituents unsupported by adequate written description, the rejection of these claims remains valid.
It is noted for the record that Applicant’s remarks are directed primarily to argument rather than to amendment of the claims. With the exception of claim 1, the claims subject to this rejection have not been amended to narrow the scope of the claims, and the arguments presented do not identify any additional disclosure in the specification from further consideration, beyond the compounds already considered in the original rejection being traversed. Absent either an amended claim set, narrowing the scope to that which is actually supported by the specification, or identification of specific disclosures not previously addressed, Applicant’s arguments are not persuasive, and do not overcome the rejection.
Genentech, 108 F.3d at 1366, states that “a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion” and “[p]atent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable”.
Accordingly, applicant has not demonstrated the possession of the claimed compounds as required under 35 U.S.C. § 112 (a). The rejection is therefore maintained. Applicant is invited to amend the claims to correspond to subject matter that is adequately supported by the specification, or to provide persuasive evidence demonstrating possession of the claimed compounds as of the effective filing date.
With respect to the rejection of claims 13-15 under 35 U.S.C. § 112 (a) for lack of enablement for a bifunctional compound of Formula (I) for use in the prevention of cancer overexpressing PXR nuclear receptor, Applicant’s amendments and arguments have been fully considered but are not persuasive for the reasons set forth below. The arguments made by Applicant are herein addressed as follows.
Applicant argues that the term “prevention” in the context of the claims is properly understood to refer to the prevention of cancer relapse, or recurrence in patients who have already been diagnosed with the specific forms of cancer, and not to the primary prevention of cancer in the general population. Applicant argues that the American Cancer Society statement cited by the office does not apply to relapse in patients with identified cancer driven by PXR overexpression.”
Applicant’s argument is found unpersuasive, because the specific rejection is centered on the lack of support for the specification showing that the claimed compounds are capable of any form of cancer prevention. The specification does not include any clinical, or in vivo data showing that degrading PXR actually prevents the incidence of primary cancer, relapse of cancer, or recurrence in an already treated cancer patient, is covered by the broad recitation of “prevention” in the instant claim. Even in consideration of the teachings of Bansard et al. (Oncogenisis, Volume 14, Issue 43, published August 30, 2025), hereinafter Bansard, co-authored by the Applicants of the instant application, the broad recitation of “prevention” is not enabled. The disclosure is centered only on the “delay” of colon cancer relapse (Title). The teaching of reduction of cancer stem cell self-renewal capacity, or sensitizing tumor cells to chemotherapy is not evidence that any form of cancer is prevented. Specifically with regard to the prevention of cancer recurrence, the American Cancer Society maintains “There’s no sure way to prevent cancer from coming back after treatment, but you can lower your risk.” The American Cancer Society focuses on diet, vitamins and supplements, physical activity, and absence from tobacco as methods to prevent cancer recurrence (American Cancer Society, “What is Cancer Recurrence?” https://www.cancer.org/cancer/survivorship/recurrence.html). Narrowing the construction of “prevention” from primary prevention to secondary prevention (especially by way of argument alone) does not cure the absence of any working example or data correlating the claimed compounds with the prevention of primary or secondary incidents of the claimed species of cancer. Finally, the claims have not been amended to clarify that only cancer relapse is intended to be covered by the claims, as argued by Applicant. For the reasons set forth above, “prevention” as recited in the instant claims remains unsupported. Accordingly, the rejection is hereby maintained.
With respect to the rejection of claims 13-15 under 35 U.S.C. § 112 (a) for a lack of enablement for a bifunctional compound of formula (I) for use in the treatment of any cancer overexpressing PXR nuclear receptor, Applicant’s amendments and arguments have been fully considered.
The amendment to claim 13 to recite “the treatment and/or prevention of colon adenocarcinoma, hepatoma, or metastatic pancreatic adenocarcinoma overexpressing the PXR nuclear receptor” sufficiently narrows the claim. The disclosure of Bansard, co-authored by the Applicants of the instant application supports the treatment of said species of cancer. Accordingly, the rejection is on the grounds of the treatment of the specified species of cancer is hereby withdrawn.
With respect to the rejection of claim 10 under 35 U.S.C. § 112 (b) as being indefinite for lack of antecedent basis, the claim amendments made by Applicant are insufficient to overcome the rejection for the reasons set forth below.
The claim continues to lack antecedent basis, because the limitation of L2 is found only in claim 7, which does not relate to the method to which claim 10 is drawn. Claim 10 depends from claim 9, and claim 9 depends from the compound of claim 1. Neither claim nine nor claim one recites or defines an element called L2. The definition of this term is introduced in claim 7, a claim that is not in the chain of dependency of claim 10. Because claim 10 depends from claim 9, and not from claim 7, there is no antecedent basis for the limitation of L2 anywhere in the claims from which claim 10 actually depends. A dependent claim must incorporate all the limitations of the claim to which it refers. It cannot import an element from an entirely different claim (and especially not a claim drawn to an entirely different invention) to supply a definition for a term with no antecedent basis is owned dependency chain. Accordingly, the rejection is hereby maintained.
With respect to the rejection of claims 1 and 13 under 35 U.S.C. § 102 (a) (1) as being anticipated by Chai et al (Med Res Rev, Volume 40, pages 1061–1083), hereinafter Chai, the claim amendments made by Applicant have removed the disclosure by Chai from consideration as a prior art rejection on the grounds of anticipation. Accordingly, the rejection is hereby withdrawn.
With respect to the rejection of claims 2, 14, and 15 under 35 U.S.C. § 103 as being unpatentable over Chai (see earlier citation) as applied to claim 1, above, in view of Benod et al. (Bioorg Med Chem, Volume 16, pages 3537-3549, published February 13, 2008, cited on Applicant IDS dated 11/17/2023), hereinafter Benod, the cancellation of claim 2 has rendered the rejection against said claim moot. Regarding the remainder of the claims, the claim amendments made by Applicant have necessitated the amendment of the original rejection. However, the combination of the teachings of the references continues to meet all the limitations of the claims, and the rejection is not overcome by amendment. Namely, a person having ordinary skill in the art following the teachings of Chai would have found it prima facie obvious to use a known highly-active compound known to bind to PXR taught by Benod into a dual PROTAC compound in an order to develop an effective PXR-targeted compound in order to degrade the well-known disease target. Applicant’s arguments are addressed as follows.
Applicant argues that the allowed claim 11 is a synthetic precursor to the compound of claim 1, constituting the entire L(PXR)-containing fragment of the bifunctional molecule. Applicant argues that amended claim 1 therefore incorporates the structural feature determined to be allowable over the prior art.
Applicant’s argument is found unpersuasive because, as instantly recited, claim 1 reads on L(PXR)-containing fragments beyond those recited in claim 11, which are covered by the combination of the teachings of Chai and Benod, as described in the amended rejection under 35 U.S.C. § 103, included hereinafter. The rejection is amended, incorporating the arguments originally applied for anticipation towards a new ground of rejection arguing the obviousness of the instant claims.
Thus, all arguments presented by Applicants have been addressed and are found unpersuasive for the reasons presented herein and in the previous non-final rejection. Applicants are reminded that “attorney argument [is] not the kind of factual evidence that is required to rebut a prima facie case of obviousness.” In re Geisler, 116 F.3d 1465, 1470 (Fed. Cir. 1997). The arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965).
Specification
The disclosure is objected to because of the following informalities:
Throughout the disclosure, several low-resolution and warped images of the two-dimensional chemical structures disclosed are included (see pages 3-7).
With respect to low-resolution images, throughout the specification, two-dimensional structures appear with a gray background behind the structures. For example, on page 7:
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With regard to warped images, the aspect ratio is not consistent among several of the structures, and the compounds look as if they have an improperly resized. For example, on page 6 of the instant specification appears the following warped image:
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In contrast to a properly sized image on page 4:
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The vast majority of the structures disclosed within the instant specification are warped in this way. Appropriate correction is required.
Drawings
The drawings filed on 06/30/2026 are found to be in compliance with 37 CFR §§ 1.121 and 1.84, and are hereby accepted.
Claim Objections
Claims 1, 3, 5, 6, and 8 are objected to for the use of low-resolution images of the two-dimensional chemical structures disclosed. Furthermore, the images used to describe the chemical structures is not consistent with the rest of the claim set. Applicant is kindly requested to include images of higher resolution and clearer images to describe the chemical structures.
Claim Rejections - 35 U.S.C. § 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.
Claims 1, 3-7, 9, 10, and 12-15 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 claims contain 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.
Claims 1, 3-7, 9, 10, and 12-15 of the instant application are drawn to compounds having the following substituents:
X’ is —C(O)— or —CH2—;
Y represents H or a C1-C6 alkyl group;
Linker represents a C1-C20 alkylene group, optionally interrupted or optionally terminating at either and/or both ends, by one of the groups —O—, —S—, —N(R′)—, —C(O)—, —C(O)O—, —OC(O)—, —OC(O)O—, —C(NOR′)—, —C(O)N(R′)—, —C(O)N(R′)C(O)—, —C(O)N(R′)C(O)N(R′)—, —N(R′)C(O)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)O—, —OC(O)N(R′)—, —C(NR′)—, —N(R′)C(NR′)—, —C(NR′)N(R′)—, —N(R′)C(NR′)N(R′)—, —S(O)2—, —OS(O)—, —S(O)O—, —S(O)—, —OS(O)2—, —N(R′)S(O)2—, —S(O)2N(R′)—, —N(R′)S—, —S(O)N(R′)—, —N(R′)S(O)2N(R′)—, —N(R′)S(O)N(R′)—, C3-C12 carbocyclene, 3-to-12-membered heterocyclene comprising 1, 2 or 3 heteroatoms selected from N, O, S, 5-to-12-membered heteroarylene comprising 1, 2 or 3 heteroatoms selected from N, O, S, or any combination thereof;
R′ represents H or a C1-C6 alkyl group;
Z represents H or a C1-C6 alkyl group;
L1 and L2 represent an alkylene group of 1 to 12 carbon atoms optionally interrupted or terminating by a 3-to-12-membered heterocyclene comprising 1, 2 or 3 heteroatoms selected from N, O, S;
35 U.S.C. § 112(a) and the first paragraph of pre-AIA 35 U.S.C. § 112 require that the "specification shall contain a written description of the invention ...." This requirement is separate and distinct from the enablement requirement. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010) (en banc); Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1560, 19 USPQ2d 1111,1114 (Fed. Cir. 1991); see also Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920-23, 69 USPQ2d 1886, 1890-93 (Fed. Cir. 2004) (discussing the history and purpose of the written description requirement); In re Curtis, 354 F.3d 1347, 1357, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004) ("conclusive evidence of a claim’s enablement is not equally conclusive of that claim’s satisfactory written description"). The written description requirement has several policy objectives. "[T]he ‘essential goal’ of the description of the invention requirement is to clearly convey the information that an applicant has invented the subject matter which is claimed." In re Barker, 559 F.2d 588, 592 n.4, 194 USPQ 470, 473 n.4 (CCPA 1977). Another objective is to convey to the public what the applicant claims as the invention. See Regents of the Univ. of Cal. v. Eli Lilly, 119 F.3d 1559, 1566, 43 USPQ2d 1398, 1404 (Fed. Cir. 1997), cert, denied, 523 U.S. 1089 (1998). "The ‘written description’ requirement implements the principle that a patent must describe the technology that is sought to be patented; the requirement serves both to satisfy the inventor’s obligation to disclose the technologic knowledge upon which the patent is based, and to demonstrate that the patentee was in possession of the invention that is claimed." Capon v. Eshhar, 418 F.3d 1349, 1357, 76 USPQ2d 1078, 1084 (Fed. Cir. 2005). Further, the written description requirement promotes the progress of the useful arts by ensuring that patentees adequately describe their inventions in their patent specifications in exchange for the right to exclude others from practicing the invention for the duration of the patent’s term.
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116.
An applicant shows possession of the claimed invention by describing the claimed invention with all of its limitations using such descriptive means as words, structures, figures, diagrams, and formulas that fully set forth the claimed invention. Lockwood v. Amer. Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997). Possession may be shown in a variety of ways including description of an actual reduction to practice, or by showing that the invention was "ready for patenting" such as by the disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the applicant was in possession of the claimed invention. See, e.g., Pfaffv. Wells Bees., Inc., 525 U.S. 55, 68, 119 S.Ct. 304, 312, 48 USPQ2d 1641, 1647 (1998); EliLilly, 119 F.3d at 1568, 43 USPQ2d at 1406; Amgen, Inc. v. Chugai Pharm.,927 F.2d 1200, 1206, 18 USPQ2d 1016, 1021 (Fed. Cir. 1991). An application specification may show actual reduction to practice by describing testing of the claimed invention.
In the present case, the important factors leading to a conclusion of inadequate written description is the absence of any working example of the invention as claimed, and the lack of predictability in the art.
In the instant specification, there is no disclosure of compounds having the following claimed substituents:
X’ as —CH2—;
Y as a C1-C6 alkyl group;
Linker as a C1-C7 or C16-C20 alkylene group optionally interrupted or optionally terminating at either and/or both ends, by one of the groups —O—, —S—, —N(R′)—, , —C(O)O—, —OC(O)—, —OC(O)O—, —C(NOR′)—, —C(O)N(R′)—, —C(O)N(R′)C(O)—, —C(O)N(R′)C(O)N(R′)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)O—, —OC(O)N(R′)—, —C(NR′)—, —N(R′)C(NR′)—, —C(NR′)N(R′)—, —N(R′)C(NR′)N(R′)—, —S(O)2—, —OS(O)—, —S(O)O—, —S(O)—, —OS(O)2—, —N(R′)S(O)2—, —S(O)2N(R′)—, —N(R′)S—, —S(O)N(R′)—, —N(R′)S(O)2N(R′)—, —N(R′)S(O)N(R′)—, C3-C12 carbocyclene, 3-to-5 or 7-to-12-membered heterocyclene comprising 1, 2 or 3 heteroatoms selected from N, O, S, 5-to-12-membered heteroarylene comprising 1, 2 or 3 heteroatoms selected from N, O, S, or any combination thereof;
R′ as a C1-C6 alkyl group;
Z as a C1-C6 alkyl group;
L1 as an alkylene group of 8 to 12 carbon atoms optionally interrupted or terminating by a 3-to-12-membered heterocyclene comprising 1, 2 or 3 heteroatoms selected from N, O, S;
L2 as an alkylene group of 8 to 12 carbon atoms optionally interrupted or terminating by a 3-to-12-membered heterocyclene comprising 1, 2 or 3 heteroatoms selected from N, O, S;
The instant specification (pages 12-15 and 24-42) teaches compounds which are characterized as having only the following substituents:
X’ is —C(O)—;
Y is H;
R′ is H;
Z is H;
L1 is an alkylene group of 1 to 7 carbon atoms;
L2 is an alkylene group of 1 to 7 carbon atoms optionally interrupted or terminating by a 6-membered heterocyclene comprising 1or 2 N heteroatoms;
Therefore, the compounds described in the instant specification detail only a limited number of the total substituents claimed (see substituents 1-6, above). All working examples presented in the instant specification are related to the compounds containing a fraction of the total claimed substituents (see substituents 14-19, above).
Regarding claims 1, 9, 10 and 12-15, the claims are inclusive of essentially any linker and any ligand capable of binding to PXR and not to the specific ligands, linkers, or bifunctional compounds disclosed in the specification or claims. Thus, Applicant claims subject matter for which possession has not been shown. For example, the L(PXR) may be a compound other than that of Formula (II), which is, at present, unsupported by the instant specification. The same is true for L(E3 ligase) and the Linker. Therefore, the subject matter of the specific instant claims remains unsupported by the specification, as no evidence of possession has been provided for that which is claimed.
There are limited working examples in the instant specification for the wide range of linkers, ligands, and substituents claimed, but for which evidence of possession has not been provided (see substituents 7-13, above). Thus, the instant specification does not provide any evidence that Applicant was in possession of the claimed invention prior to the effective filing of the instant application.
Vas-Cath Inc. Mahurkar, 19 USPQ2d 1111, makes clear the "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. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed" (see page 1117). The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed" (see Vas-Cath at page 1116).
Finally, University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404, 1405 held that: ...To fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines, Inc., 107 F. 3d 1565, 1572, 41 USPQ2d 1961, 1966(1997); In re Gosteli, 872 F.2d 1008, 1012,10 USPQ2d 1614, 1618 (Fed Cir. 1989) ("[T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed.") Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d at 1966.
It is noted that the pharmaceutical art is unpredictable, requiring each embodiment to be individually assessed for physiological activity. For inventions in emerging and unpredictable technologies, or for inventions characterized by factors not reasonably predictable which are known to one of ordinary skill in the art, more evidence is required to show possession. For example, disclosure of only a method of making the invention and the function may not be sufficient to support a product claim other than a product-by-process claim. See, e.g., Fiers v. Revel, 984 F.2d at 1169, 25 USPQ2d at 1605; Amgen, 927 F.2d at 1206, 18 USPQ2d at 1021.
Thus, since Applicant has not described in adequate detail methods to synthesize compounds containing the claimed substituents, or provided evidence that said compounds have been characterized, or that they exist, an ordinary skilled artisan could not completely envisage Applicants’ invention. Moreover, it is clear that the written description requirement has not been met since Applicant has not provided any evidence that Applicant was in possession of the claimed invention prior to the effective filing of the instant application. Thus, claims 1, 3-7, 9, 10, and 12-15 of the instant application are not supported by the instant specification and thus a rejection under 35 U.S.C. § 112 (a) for failing to comply with the written description requirement is proper.
Claims 13-15 are rejected under 35 U.S.C. § 112 (a), or 35 U.S.C. § 112 (pre-AIA ) first paragraph, because the specification, while being enabling a bifunctional compound of formula (I) for the degradation of PXR, it does not reasonably provide enablement for a bifunctional compound of formula (I) for use in the prevention of colon adenocarcinoma, hepatoma, or metastatic pancreatic adenocarcinoma overexpressing PXR nuclear receptor. The specification does not provide sufficient information to support the claim as recited.
The instant specification fails to provide information that would allow the skilled artisan to fully practice the instant invention without undue experimentation. Attention is directed to In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors, which are considered in determining whether undue experimentation is required to practice the invention:
(1) Nature of the invention;
(2) Breadth of the claims;
(3) State of prior art;
(4) Level of ordinary skill in the art;
(5) Level of predictability in the art;
(6) Amount of direction provided;
(7) Presence of working examples; and
(8) Quantity of experimentation required to make or use the invention.
In re Wands, 858 F.2d 731, 737 (Fed. Cir. 1988).
All of the Wands factors have been considered with regard to the instant claim, with the most relevant factors discussed below.
Nature of the invention: Claim 13 of the instant application is drawn to a compound useful in the treatment and/or prevention of colon adenocarcinoma, hepatoma, or metastatic pancreatic adenocarcinoma overexpressing PXR nuclear receptor.
Breadth of the claims: The complex nature of the subject matter of this invention is greatly exacerbated by the breadth of the claims. The rejected claims are extremely broad. Applicant claims that the claimed compounds can be used to treat a subject having, suspected of having, or at risk of developing colon adenocarcinoma, hepatoma, or metastatic pancreatic adenocarcinoma overexpressing PXR nuclear receptor. Thus, the cited claims are deemed very broad since these claims read on essentially preventing any colon adenocarcinoma, hepatoma, or metastatic pancreatic adenocarcinoma related to the overexpression of PXR nuclear receptor comprising the administration of a compound of Formula (I), which includes subjects at risk of developing a broad range of cancers.
State of the Prior Art: While the state of the art with regard to the treatment of cancer is relatively high, the state of the art with regard to the prevention of cancer is underdeveloped. This is because there would be no way to determine whether cancer would have predictably occurred without treatment.
Regarding prevention of cancer, the American Cancer Society maintains that “There's no sure way to prevent cancer, but you can help reduce your risk by making healthy choices like eating right, staying active, and not smoking” (American Cancer Society. Cancer Risk and Prevention. https://www.cancer.org/cancer/risk-prevention.html).
Regarding the prevention of cancer recurrence, the American Cancer Society maintains “There’s no sure way to prevent cancer from coming back after treatment, but you can lower your risk.” The American Cancer Society focuses on diet, vitamins and supplements, physical activity, and absence from tobacco as methods to prevent cancer recurrence (American Cancer Society, “What is Cancer Recurrence?” https://www.cancer.org/cancer/survivorship/recurrence.html)
With regard to the compounds instantly claimed, according to Bansard et al (Oncogenisis, Volume 14, Issue 43, published August 30, 2025), hereinafter Bansard, the state of the art demonstrates that the instantly claimed bifunctional compound is capable of degrading PXR in selected cancer cell lines—colon adenocarcinoma, hepatoma, and metastatic pancreatic adenocarcinoma cells (pages 4-11). It is proposed as a therapeutic strategy for chemo resistant cancers, especially in the context of colon adenocarcinoma, hepatoma, and metastatic pancreatic adenocarcinoma cancer types. The disclosure therefore supports relationship between the PROTAC and treatment of certain PXR-associated chemo resistant cancers. Furthermore, the disclosure supports the delay of colon cancer relapse (Title, Abstract, pages 8 and 9). However, the disclosure the PROTAC prevents the development of a recurrence of any form of cancer overexpressing PXR nuclear receptors. That is, the disclosure demonstrates that the instantly claimed compounds may be capable of successful treatment of colon adenocarcinoma, hepatoma, and metastatic pancreatic adenocarcinoma which overexpress PXR nuclear receptors and not the prevention of these cancers. In support of the argument of limited efficacy of the compounds, Bansard reports that JMV7048, a PXR-targeted PROTAC is not capable of degrading PXR in human hepatocytes (Figure 4 and page 6). As such, the state of the prior art demonstrates that the instantly claimed compounds may treat a limited number of cancers overexpressing PXR nuclear receptors, and the prevention of the claimed cancers expressing PXR nuclear receptors, as instantly claimed.
Predictability/Unpredictability in the Art: It is noted that the pharmaceutical art is unpredictable, requiring each embodiment to be individually assessed for physiological activity in preventing diseases. In re Fisher, 427 F.2d 833, 166 USPQ 18 (CCPA 1970) indicates that the more unpredictable an area is, the more specific enablement is necessary in order to satisfy the statute. In the instant case, the instant claimed invention is highly unpredictable since one skilled in the art would recognize that the recitation encompasses the prevention and treatment of subjects and risk of developing and those subjects suspected of having of colon adenocarcinoma, hepatoma, or metastatic pancreatic adenocarcinoma overexpressing PXR nuclear receptor. Thus, the skilled artisan would view that the prevention of all colon adenocarcinoma, hepatoma, or metastatic pancreatic adenocarcinoma overexpressing PXR nuclear receptor as encompassed by the claims, by administering a compound of Formula (I), is highly unpredictable.
Guidance of the Specification/Working Examples: Applicant has only provided working examples suggesting that compounds of Formula (I) may degrade PXR in vivo and that PROTACs may be used in chemoresistant colic cancer stem cells. Thus, the specification fails to provide sufficient evidence in support of prevention or treatment of those suspected of having or at risk of developing colon adenocarcinoma, hepatoma, or metastatic pancreatic adenocarcinoma overexpressing PXR nuclear receptor as recited in the instant claims.
Additionally, the examples provided do not demonstrate the prevention of any cancer. The disclosure does not discuss, or demonstrate through working examples, a method that could be used to determine that recurrence of diseases/disorders was prevented using the claimed agents as there is no disclosed method to determine that recurrence of cancer or any of the aforementioned diseases would have predictably occurred without treatment.
The Quantitation of Experimentation Required: In order to practice Applicants invention, it would be necessary for one to design and conduct an exhaustive amount of complex experiments to demonstrate that the claimed compounds could be administered to a subject at risk of developing colon adenocarcinoma, hepatoma, or metastatic pancreatic adenocarcinoma overexpressing PXR nuclear receptor. The population of subjects could include any subject, and thus the quantitation of experimentation is unreasonably large. Therefore, in order to practice the claimed invention, the amount of experimentation required would be considered undue and burdensome.
In conclusion, Genentech, 108 F.3d at 1366, states that “a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion” and “[p]atent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable”. A compound of Formula (I) for use in the prevention of colon adenocarcinoma, hepatoma, or metastatic pancreatic adenocarcinoma overexpressing PXR nuclear receptor is not enabled by the instant specification.
Claim Rejections - 35 U.S.C. § 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.
Claim 10 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 10 recites, “wherein L2 and L(E3 ligase) are as defined according to claim 7.” It has been determined that there is insufficient antecedent basis for the limitation (L2) in the claim. The limitation of L2 is found only in claim 7, which does not relate to the method to which claim 10 is drawn. Claim 10 depends on claim 9, and claim 9 depends on the compound of claim 1. Neither claim 9 nor claim 1 recites or defines an element called L2. The definition of this term is introduced in claim 7, a claim that is not in the chain of dependency of claim 10. Because claim 10 depends from claim 9, and not from claim 7, there is no antecedent basis for the limitation of L2 anywhere in the claims from which claim 10 actually depends. A dependent claim must incorporate all the limitations of the claim to which it refers. It cannot import an element from an entirely different claim (and especially not a claim drawn to an entirely different invention) to supply a definition for a term with no antecedent basis is owned dependency chain.
Claim Rejections - 35 U.S.C. § 103
The following is a quotation of pre-AIA 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.
Claims 1 and 12-15 are rejected under 35 U.S.C. § 103 as being unpatentable over Chai et al (Med Res Rev, Volume 40, pages 1061–1083), hereinafter Chai in view of Benod et al. (Bioorg Med Chem, Volume 16, pages 3537-3549, published February 13, 2008, cited on Applicant IDS dated 11/17/2023), hereinafter Benod.
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[AltContent: connector][AltContent: textbox (Figure 1. Bifunctional compound: PXR-targeting linked to machinery for degradation by E3 Ligase by PROTACs as taught by Chai)]The instant claims are drawn to a bifunctional compound having the general Formula (I), made up of a ligand capable of binding to the PXR nuclear receptor, a ligand of the E3-ubiquitin ligase, and group which makes it possible to link the two ligands to each other. The claims are further drawn to the specific ligand L(PXR) capable of binding to the PXR nuclear receptor, wherein the compound is of Formula (II) (left, above).
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[AltContent: textbox (Fig 1. a) A bifunctional compound targeting PXR, linked to recruiting machinery E3 ubiquitin ligase by PROTACs (see Figure 5D and caption, page 1076 of Chai))]Chai teaches the development of Pregnane X receptor (PXR) antagonists, and discusses the principal challenges and proposed development approaches (Title, Abstract). One of the development strategies discussed by Chai is the use of PROTACs to couple PXR ligands to recruit machinery for degradation, such as the recruitment of E3 ubiquitin ligase (Figure 5D, page 1076). Within the Figure, the PXR ligand is linked to a protein for degradation using a linker (see Figure 5D reproduced, above).
Chai fails to teach wherein the specific ligand capable of binding to PXR in a bifunctional -PROTAC is that of Formula (II).
The deficiencies of Chai are remedied by Benod, who teaches N-1H-Benzimidazol-5-ylbenzenesulfonamide derivatives as potent hPXR agonists (Title). Specifically, Benod teaches CAS Registry Number: RN 1026754-80-2. [Database Registry Chemical Abstracts Service, Columbus, Ohio, Accession No. RN 1026754-80-2, Entered STN: 09 Jun 2008] (Table 3,
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compound 6m, left). Benod reported a sharp increase in potency through the introduction of three methyl groups on the phenyl ring of R5, with a resulting EC50 of 1.5 nM. The compound 6m was shown to be one of the most highly active (see section 3.3, page 3544). The disclosure identified N-1H-benzimidazol-5ylbenzenesulfonamide scaffold that allows for the design of potent PXR agonist ligands (page 3545).
Prior to the filing of the instant application, a person having ordinary skill in the art following the teachings of Chai would have found it prima facie obvious to use a known, highly-active compound known to bind to PXR taught by Benod into a dual PROTAC compound in an order to develop an effective PXR-targeted compound in order to degrade the well-known disease target.
Regarding claim 13, wherein the compound of claim is for use in the treatment and/or prevention of cancer over expressing the PXR nuclear receptor, this is merely recitations of intended use of the compound. According to MPEP § 2112.01 (I), 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. The courts have stated,
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. “See In re Spada "Products of identical chemical composition cannot have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. Id. (Applicant argued that the claimed composition was a pressure sensitive adhesive containing a tacky polymer while the product of the reference was hard and abrasion resistant. "The Board correctly found that the virtual identity of monomers and procedures sufficed to support a prima facie case of unpatentability of Spada’s polymer latexes for lack of novelty.").
Therefore, if the prior art structure is capable of performing the intended use, the prior art is capable of performing the claimed use, and thus, meets the claims.
Regarding claims 12, 14, and 15, Chai teaches that PROTACs targeting the degradation of PXR may be useful in the treatment of cancer. Furthermore, Chai explicitly teaches that the administration of PXR-directed therapy with an anticancer agent might be useful in therapeutics that can be co-administered with other drugs that activate PXR (page 1076), specifically identifying paclitaxel as a relevant PXR-targeting therapy (1065), in order to reduce PXR-mediated drug resistant and toxicity. Thus, the reference explicitly teaches that inhibition of PXR is useful in combination with anticancer therapy to address cancer drug resistance, and alludes to the use of excipients for administration
Regarding claims 14 and 15, Chai further teaches that PXR is implicated in cancer drug resistance because PXR activation induces resistance to chemotherapeutic agents used to treat cancer (page) and enhances the drug metabolizing pathway to reduce the sensitivity of tumor cells to chemotherapeutic agents (page 1062). Chai teaches that PX art antagonists may be co-administered with other drugs activate PXR, highlighting that such antagonists are being developed as co-drugs to prevent or overcome cancer drug resistance (page 1075).
Further regarding claim 14, according to MPEP 2144.06 (I), combining equivalents known for the same purpose is rendered obvious. The courts have said,
It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (Claims to a process of preparing a spray-dried detergent by mixing together two conventional spray-dried detergents were held to be prima facie obvious.).
According to the teachings of Chai as set forth above, a PXR-targeting PROTAC and an anticancer drug are equivalents that would be used for the same objective—cancer treatment and mediating drug resistance. Therefore, a person of ordinary skill in the art prior to the filing of the instant application would have found it obvious to combine a PROTAC which degrades or otherwise inhibits PXR with an anticancer drug, as both are found to be used for a common purpose, i.e., treating cancer and preventing or overcoming PXR-mediated cancer drug resistance.
Conclusion
Claims 1, 3, 5, 6, and 8 are objected to.
Claims 1, 3-7, 9, 10, and 12-15 are rejected.
Claim 11 was previously allowed.
Applicant's amendment necessitated the new grounds 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.
Correspondence
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/SOPHIA P HIRAKIS/Examiner, Art Unit 1623
/VALERIE RODRIGUEZ-GARCIA/Primary Examiner, Art Unit 1621
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