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 .
The claims filed 11/24/2025 are under consideration.
Election/Restrictions
Applicant's election with traverse of Group I, claims 1, 24, 26, 31, 33, 35, 37, 43, 47, 54, 67, 71, 73, 77, 83, 87-90, 107, 134-137, 139, 140, 143, 146-148, 152, 160, 165, 168, 173, 176, 177, 179, and 181-182, in the reply filed on 11/24/2025 is acknowledged. The traversal is on the ground(s) that Iwata (WO 2018/110515 A1) does not teach the ADC of the amended claims and measuring gene expression. This is not found persuasive because a lack of unity exists over the amended claims for the following reasons. Bekos (Cancers. 2019. 11:698) teaches that enfortumab vedotin is a known treatment for Nectin-4 expressing cancers (p. 17-18 of 27). Enfortumab vedotin is encompassed by the ADC in the amended claims as evidenced by the instant specification (paras. 502 and 738). Bekos further teaches determining the expression level of numerous “ADC Set I Markger genes” are down-regulated prior to treatments as explained below. As explained in the restriction requirement, Iwata teaches administering an ADC and measuring the expression of genes, such as MHC I (para. 268-274, 275-277 and 285). Thus, it would have been prima facie obvious to the ordinary artisan to have treated the cancer patients in Bekos with Enfortumab vedotin and to have monitored for increases in the expression of the genes down-regulated in Nectin-4 expressing tumors. The increase would result from the loss of the Nectin-4 expressing cells, rending the tumor to have the gene expression profile of a tumor that does not express Nectin-4 or one that expresses low levels of Nectin-4. See Bekos, comparing gene expression between tumors being negative for Nectin-4, low expressin of Nectin-4 and high expression of Nectin-4.
The requirement is still deemed proper and is therefore made FINAL.
Claims 1(II)-1(IV), 109, 110, 156, 160 and 165 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected inventions, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 11/24/2025.
The following election of species requirements have been reconsidered and are withdrawn: A, B, C, D, F, H, I, K, L and M.
Applicant elected the following species:
E. An immune checkpoint inhibitor of claim 110 – anti-PD-1 antibody
G. An tubulin disrupting agent of claim 18, 143, 146, and 147 - MMAE
J. A first dose and a second dose of claim 160 and 165 - a first dose of the ADC is a dose of about 1.25 mg/kg of the subject's and a second dose of about 0.25 mg/kg.
Priority
The present application is a 371 national stage entry of PCT/US21/37994 (filed 6/18/2021), which claim benefit of US provisional application 63/041,636 (filed 6/19/2020).
Priority is recognized.
Information Disclosure Statement
The listing of references in the specification or the citation of references throughout the body of the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892 or cited on a submitted IDS, they have not been considered.
Claim Objections
Claim 1 is objected to because of the following informalities: claim 1 is overly complex because it has a preamble with 4 parts and sets forth 4 different methods. The first two steps of the different methods are substantially similar and are repetitive and the third step of the methods differ, but may be consolidated to make the claim more concise. Furthermore, there is no clear relationship between the 4 parts of the preamble and the 4 different methods in the body of the claim.
Appropriate correction is required.
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.
Claims 1, 24, 26, 31, 33, 35, 37, 43, 47, 54, 67, 71, 73, 77, 83, 87, 88, 89, 90, 107, 134, 135, 137, 139, 140, 143, 146, 147, 148, 152, 168, 173, 176, 177, 179, 181 and 182 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.
Claim 1 is drawn to methods. The claim requires a step of “determining an increase of expression of one or more ADC Set I Marker genes”. The term “ADC Set I Marker genes” is detailed in claim 1 as comprising “one or more major histocompatibility complex (MHC) signature genes, one or more toll-like receptor (TLR) family genes, one or more interleukin receptor family genes, one or more immune checkpoint receptor genes, one or more receptor tyrosine kinase genes, one or more IFN receptor family genes, one or more TNF family receptor genes, one or more inhibitory immunoreceptor genes, and/or one or more metabolic enzyme genes”. The instant specification provides a similar definition in para. 314:
the term "ADC Set I Marker genes" refers to any set or subset of the follow group of genes: MHC signature genes, TLR family genes, interleukin receptor family genes, immune checkpoint receptor genes, receptor tyrosin kinase genes, IFN receptor family genes, TNF family receptor genes, inhibitory immunoreceptor genes, and/or metabolic enzyme genes, each as defined herein, in any combination or permutation.
Dependent claim 87 requires a step of “determining an increase of expression of one or more ADC Set II Marker genes in the subject”. The claim does not describe the scope of what is an “ADC Set II Marker gene”. The instant specification provides a definition in para. 327 provides the following definition:
the term "ADC Set II Marker genes" is intended to mean genes that have both attributes of: (1) which are not ADC Set I Marker genes and (2) whose expression correlates with the increase in immunogenic cell death (ICD).
The instant specification states that in a nude mouse, xenograft model using bladder cancer cell lines engineered to express Nectin-4, 1267 genes were identified as being differentially regulated genes, i.e., went up or down between the untreated samples versus samples treated with enfortumab vedotin, in tumor samples or cell line samples (para. 220, 915, 921). The instant specification does not identify the 1267 genes, or which ones had expression that went up versus down. For this reason alone, the application fails the written description requirement.
Those that “went up” are relevant to the claimed methods in particular, as “determining an increase of expression of one or more ADC Set I Marker genes in the subject” is required. The instant specification does identify a subset of genes in the Figures that have differential expression between treated and untreated mice or those given a non-binding ADC (Figs. 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 and 21). The genes are a mixture of mouse (host) genes and human (transplanted tumor) genes. The genes were identified by RNA-seq, which screens the entire transcriptome. Thus, applicant is not in possession of any genes outside of the 1267 because they were not differentially expressed, and thus are not useful in the claimed methods. There is no validation of the observed genes in fully immunocompetent mice (nude mice lack T cells) or in human patients. There is no guidance as two whether patient samples other than a tumor sample, such as blood samples, normal tissue samples, etc., would be informative regarding the differential expression of any of the 1267 genes identified by applicant but not fully disclosed. The instant specification is an invitation for one to carry out an analysis to identify ADC Set I and II Marker genes, with no reasonable expectation of success that the same set of 1267 genes would be identified.
The limited number of genes specifically identified, do not reasonably provide support for the entire scope of the claimed ADC Set I and II Marker genes. The generic gene subsets described in the specification covers far more than 1267 genes, and there is no clear guidance regarding which 1267 genes applicant specifically identified and those applicant was not interested in or those that were not informative, i.e., no differential expression. Furthermore, within the identified subsets of genes encompassed by the ADC Set I and II Marker genes, e.g. MHC signature genes, TLR family genes, interleukin receptor family genes, etc., are quite broad. There is no guidance which “MHC signature genes” applicant identified as within the 1267 genes and which were not.
Claims 24, 26, 31, 33, 35, 37, 43, 47, 54, 67, 71, 73, 77, 83, 87, 88, 89, 90, 107, 134, 135, 137, 139, 140, 143, 146, 147, 148, 152, 168, 173, 176, 177, 179, 181 and 182 depend from claim 1 and are rejected for the same reason provided above.
Claim Rejections - 35 USC § 112
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, 24, 26, 31, 33, 35, 37, 43, 47, 54, 67, 71, 73, 77, 83, 87, 88, 89, 90, 107, 134, 135, 136, 137, 139, 140, 143, 146, 147, 148, 152, 168, 173, 176, 177, 179, 181 and 182 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.
Regarding claim 1, the preamble of the claim sets forth 4 different intended uses. The body of the claim sets forth 4 distinct methods. None of which clearly relate to a particular intended use or to the group of intended uses a whole. It is unclear if the methods require more in order to accomplish the various intended uses set forth in the preamble.
Regarding claim 1, the claim recites “the subject” in line 1 of step (1). It is unclear if the methods are drawn to methods for “(iv) increasing expression of one or more ADC Set I Marker genes in a cancer in a subject in need thereof” because in view of the punctuation in the preamble, that is the only intended use that refers to “a subject”.
Alternatively, the recitation lacks proper antecedent basis if the intended uses are (i) to (iii) because they do not reference “a subject”.
Regarding claim 1, the claim requires a step of “determining an increase of expression of one or more ADC Set I Marker genes in the subject”. Step (3) broadly encompasses alternative steps based on whether or not “increased” expression was observed. It is unclear whether the methods encompass embodiments in which alternatives based on observing no increase expression are encompassed by the claim because the claim requires “determining” only “an increase of expression of one or more ADC Set I Marker genes in the subject”.
Claims 24, 26, 31, 33, 35, 37, 43, 47, 54, 67, 71, 73, 77, 83, 87, 88, 89, 90, 107, 134, 135, 136, 137, 139, 140, 143, 146, 147, 148, 152, 168, 173, 176, 177, 179, 181 and 182.
Regarding claim 87, the claim refers to “step (1)”. Claim 1, from which claim 87 depends, sets forth for different steps identified as “step (1)”. It is unclear which step is being further limited.
Regarding claim 88, the claim refers to “step (1)”. Claim 1, from which claim 88 ultimately depends, sets forth for different steps identified as “step (3)(a)”. It is unclear which step is being further limited.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 134, 135 and 136 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Regarding claim 134, in view of the amendments to claim 1, the claim does not further limit the scope of claim 1. Claim 1 specifies that the ADC requires SEQ ID NOs: 22 and 23. Claim 134 restates the elements of claim 1 and/or requires sequences that are outside of the scope of claim 1.
Regarding claim 135, in view of the amendments to claim 1, the claim does not further limit the scope of claim 1. Claim 1 specifies that the ADC requires SEQ ID NOs: 22 and 23. Claim 135 restates the elements of claim 1 and/or requires sequences that are outside of the scope of claim 1.
Regarding claim 136, in view of the amendments to claim 1, the claim does not further limit the scope of claim 1. Claim 1 specifies that the ADC requires SEQ ID NOs: 22 and 23. Claim 136 restates the elements of claim 1 and/or requires sequences that are outside of the scope of claim 1.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections – Improper Markush
Claim 1 is rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984).
A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
Claim 1 includes a grouping of four methods presented in the alternative. This Markush group is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: the methods are not alternative species defined based on structure, function or use. The members, which are separate methods, are not members of the same recognized physical or chemical class or the same art-recognized class.
Claims 1, 26, 33, 35, 47, 54, 71, 83, 89 and 90 include Markush groups listing genes as the alternatives. The different genes encompassed by the claims have different structures (both in terms of nucleic acid sequences and amino acid sequences) and have different functions or uses. Also, absent the specification, the sets of genes are not art-recognized as being in a class of genes relevant to treatment with the ADC described in claim 1.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
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.
Claim(s) 1, 24, 26, 31, 33, 35, 37, 43, 47, 54, 67, 71, 73, 77, 83, 87-90, 107, 134-137, 139, 140, 143, 146-148, 176 and 177 is/are rejected under 35 U.S.C. 103 as being unpatentable over Bekos (Cancers. 2019. 11:698 and Supplementary Materials; published 5/20/2019).
Regarding claims 1, 24, 26, 31, 33, 35, 37, 43, 47, 54, 67, 71, 73, 77, 83, 87-90, 176 and 177, Bekos teaches determining expression of the following genes using RNA-sequencing in ovarian tumor tissues: LST1, IFNAR1, HLA-A, IL2RA, VSIR, TLR8, TLR7, CSF1R, EDEM2, IDO1, ERP29, CD276, CIITA, REL, TNFRSF1A, IFNAR2 and IL20RA (Table S5; a truncated copy is provided listing relevant genes).
The genes were down-regulated in Nectin-4 high expressing tumors (Table S5).
Bekos further teaches that enfortumab vedotin was known as a treatment for Nectin 4 expressing cancers (p. 17-18 of 27).
It would have been prima facie obvious to have treated the patients of Bekos with enfortumab vedotin. One would have been motivated to look at gene expression after treatment to see evaluate the effectiveness of the treatment. One would reasonably infer that removing a Nectin 4-expressing cell from a tumor would make it look more like a Nectin-4 negative tumor, which has relative increases in the expression of the genes as compared to Nectin 4-expressing tumors. Furthermore, if the gene expression indicates that Nectin 4-expressing tumor cells are being reduced after treatment, it would have been prima facie obvious to continue giving enfortumab vedotin. However, if the gene expression indicates that Nectin 4-expressing tumor cells are not being reduced after treatment, it would have been prima facie obvious to stop giving the same dose of enfortumab vedotin to the patient as it is not being effective.
Regarding claim 107, one would reasonably expect that the removal of Nectin 4-expressing cells would result in tumors having gene expression that is similar to Nectin 4-negative tumors, achieving a fold increase that is encompassed by the claimed ranges.
Regarding claims 134-137, 139, 140, 143 and 146-148, as noted above Bekos teaches and suggests using enfortumab vedotin as a treatment. In view of the instant specification, enfortumab vedotin has all the elements detailed in claims 134-137, 139, 140, 143, 146, 147 and 148.
Claim(s) 152 and 168 is/are rejected under 35 U.S.C. 103 as being unpatentable over Bekos (Cancers. 2019. 11:698 and Supplementary Materials; published 5/20/2019) in view of Satpayev (US 8,637,642 B2).
Regarding claims 152 and 168, Bekos renders obvious the elements of claim 1 as described above and as required by claims 152 and 168.
Bekos does not teach the additional elements specific to claims 152 and 168.
However, Satpayev teaches aspects known about ADCs targeting 191P4D12/Nectin-4.
Regarding claim 152, Satpayev teaches that the ADC is given at a dose of 5 or 10 mg/kg (col. 70, lines 44-67).
Regarding claim 168, Satpayev teaches the ADC is administered via intravenous injection (col. 70, lines 44-67).
It would have been prima facie obvious to have delivered the enfortumab vedotin taught by Bekos based on the parameters of Satpayev demonstrating how such drugs are delivered.
Claim(s) 173 is/are rejected under 35 U.S.C. 103 as being unpatentable over Bekos (Cancers. 2019. 11:698 and Supplementary Materials; published 5/20/2019) in view of Adler (US 2015/0353640 A1).
Regarding claim 173, Bekos renders obvious the elements of claim 1 as described above and as required by claim 173.
Bekos does not teach the additional elements specific to claim 173.
However, Adler teaches formulating a pharmaceutical composition comprising an antibody by including excipients of L-histidine, polysorbate 20, and trehalose (para. 87).
It would have been prima facie obvious to one of ordinary skill at the time of filing to use the excipients as taught by Adler to formulate the enfortumab vedotin composition noted by Bekos. One of ordinary skill in the art would have been motivated to do so, because Bekos teaches a pharmaceutical composition comprising an antibody drug conjugate (ADC), and Adler further teaches formulating a pharmaceutical composition comprising an antibody by including excipients of L-histidine, polysorbate 20, and trehalose. Therefore, the combined teachings provide a reasonable expectation of success in formulating the pharmaceutical composition.
Claim(s) 179 is/are rejected under 35 U.S.C. 103 as being unpatentable over Bekos (Cancers. 2019. 11:698 and Supplementary Materials; published 5/20/2019) in view of Lopez (WO 2017/042210 A1).
Regarding claim 179, Bekos renders obvious the elements of claims 1 and 176 as described above and as required by claim 179.
Bekos does not teach the additional elements specific to claim 179.
However, Lopez teaches that Nectin 4 is mainly expressed in triple-negative breast tumors (p. 1).
It would have been prima facie obvious to the ordinary artisan to have modified the method of Bekos by using, treating and analyzing triple-negative breast tumors. One would have been motivated to do so because enfortumab vedotin targets Nectin 4 and it would have been obvious to try and target those tumors specifically.
Claim(s) 181 and 182 is/are rejected under 35 U.S.C. 103 as being unpatentable over Bekos (Cancers. 2019. 11:698 and Supplementary Materials; published 5/20/2019) in view of Mar (Journal of Oncology Practice. 2019. 15(8):421-428).
Regarding claims 181 and 182, Bekos renders obvious the elements of claims 1 and 176 as described above and as required by claims 181 and 182.
Bekos does not teach the additional elements specific to claims 181 and 182.
However, Mar teaches that Nectin 4 is overexpressed in 97% of all urothelial carcinomas (p. 425), which includes both papillary urothelial carcinoma and flat urothelial carcinoma subtypes. Urothelial carcinoma is a form of non-muscle invasive bladder cancer.
It would have been prima facie obvious to the ordinary artisan to have modified the method of Bekos by using, treating and analyzing various types of urothelial and bladder tumors. One would have been motivated to do so because enfortumab vedotin targets Nectin 4 and it would have been obvious to try and target those tumors specifically.
Conclusion
No claims allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOSEPH G DAUNER whose telephone number is (571)270-3574. The examiner can normally be reached 7 am EST to 4:30 EST with second Fridays Off.
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/JOSEPH G. DAUNER/Primary Examiner, Art Unit 1682