DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
2. Applicant’s election of Group I and the species of SDHC copy number and a bicycle toxin conjugate specific for Nectin-4 in the reply filed on 17 December 2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claim Status
3. Claims 51-72 are pending.
Claim 72 is withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claims 57, 59, 67 and 69 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim.
Claims 51-56, 58, 60-66, 68, and 70-71 read on the elected invention and have been examined herein. The claims have been examined to the extent that they read on the elected species of the SDHC gene and a bicycle toxin conjugate specific for Nection-4. The claims encompass the non-elected species of the DDR2 gene and a bicycle tumor targeted immune agonist specific for Nectin-4. Prior to the allowance of claims, any non-elected subject matter which has not been rejoined with the elected subject matter will be required to be removed from the claims.
Objection to Drawings / Objection to the Specification
4. The drawings are objected to under 37 CFR 1.83(a). The specification describes the figures in terms of particular colors; for example Figure 7D (at para [0065]; i.e., “red curve” and “blue curve”) and Figure 10B (at para [0019]; i.e. red, blue, green and cyan). However, the figures have been filed in black and white. Thus, the description of the figures in the specification is not consistent with the drawing and the specification is thereby also objected to.
If the drawings are intended to be in black and white, the specification should be amended to delete the reference to the recited colors. Alternatively, corrected drawing sheets in compliance with 37 CFR 1.121(d) are required. Note that color drawings are only accepted on rare occasions when they are the only practical medium by which to disclose the subject matter to be patented. See MPEP 608.02(VIII).
Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
If color photographs or color drawings are submitted, it is noted that color photographs and color drawings are not accepted unless a petition filed under 37 CFR 1.84(a)(2) is granted.
A petition for color drawings must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via EFS-Web or three sets of color drawings or color photographs, as appropriate, if not submitted via EFS-Web, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Appropriate correction is required.
Specification
5. The use of the term MultiOmyx™ which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
This is one example of a trademark that is used in the specification. The specification should be reviewed for any additional trademarks or trade names and the terms should be accompanied by their generic terminology and capitalized or where appropriate accompanied by a proper symbol.
Claim Rejections - 35 USC § 112(b) - Indefiniteness
6. 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 53, 58 and 61-70 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.
Claims 53 and 63 are indefinite over the recitation of “Log2 (CN ratio)” because this phrase is not defined in the claims and there does not appear to be a limiting definition for this phrase in the specification. It is acknowledged that the specification (para [0110]) states “As used herein, the term “an SDHC amplification” refers to an increase in SDHC DNA copy number over normal tissue. In some embodiments, this is expressed as Log 2 of the copy number ratio or SDHC Log 2(CN ratio).” In view of the language “in some embodiments,” and because the claim does not recite “SDHC amplification,” it is unclear as to whether the copy number ratio is with respect to that of SDHC in a normal tissue from the subject, or from any other subject or to some other unspecified copy number.
Claims 58 and 68 are indefinite over the recitation of “wherein Nectin-4-expressing tumor cells and CD 137- expressing immune cells co-localize in the tumor” because it is unclear as to how this recitation is intended to further limit the claims. Is this considered to be a property of any tumor having an SDHC copy number of more than two, or of any tumor in which SDHC copy number is measured and/or are the claims intended to require determining that the tumor comprises nectin-4 expressing tumor cells and that CD137-expressing cells are co-localized with the tumor. Note that the claims previously refer only to a tumor per so and do not previously refer to “Nectin-4-expressing tumor cells”
Claims 61-70 are indefinite over the recitation of “the patient having a SDHC…copy number of more than two” because this phrase lacks proper antecedent basis. While the claims previously recite measuring SDHC copy number in a sample from a patient having a tumor, the claims do not recite that the measuring results in the detection of a SDHC copy number more than two. The claims are considered to require performing the administering step, but it is unclear as to who the bicycle toxin conjugate is administered to since the claim does not recite a patient having a SDHC copy number of more than two. Further, while claim 62 recites detecting a SDHC copy number of more than two, the claim does not recite a nexus between the measuring and detecting steps and does not require that the measuring and detecting occur prior to the administering step.
Claim Rejections - 35 USC § 112 first paragraph – Written Description
7. 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 51-55, 58, 60-65, 68, and 70-71 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a Written Description rejection.
In analyzing the claims for compliance with the written description requirement of 35 U.S.C. 112, first paragraph, the written description guidelines note that with regard to genus/species situations, a “Satisfactory disclosure of a “representative number'' depends on whether one of skill in the art would recognize that the applicant was in possession of the necessary common attributes or features of the elements possessed by the members of the genus in view of the species disclosed.”
The claims are drawn to methods that require administering a bicycle toxin conjugate specific for Nectin-4 to a subject selected as having a SDHC copy number of more than two in a tumor.
The claims do not define the bicycle toxin conjugate specific for Nectin-4 in terms of their complete structure or in terms of any other relevant structural properties. The claims encompass methods that require a potentially large genus of undefined compounds for the treatment of a subject having a tumor.
The specification teaches only the bicycle toxin conjugate specific for Nectin-4 of BT8009 set forth on p. 17 of the specification.
The specification (para [0069-0070]) states:
“As used herein, the term “a Bicycle toxin conjugate specific for Nectin-4” refers to a Bicycle toxin conjugate that binds specifically to Nectin-4. Various Bicycle toxin conjugates specific for Nectin-4 have been described previously, for example, in US 2019/03889906, WO 2019/243832, and WO 2019/243833, the content of each of which is incorporated herein by reference in its entirety. BT8009 is referred to as BCY8245 in US 2019/03889906, WO 2019/243832, and WO 2019/243833.
The term “BT8009,” as used herein, is a Bicycle toxin conjugate having a structure as shown below, or a pharmaceutically acceptable salt thereof, wherein the molecular scaffold is 1,1′,1″-(1,3,5-triazinane-1,3,5-triyl)triprop-2-en-1-one (TATA), and the peptide ligand comprises the amino acid sequence:
(β-Ala)-Sar10-CiP[1Nal][dD]CiiM[HArg]DWSTP[HyP]WCiii(SEQ ID NO: 1)
wherein Sar is sarcosine, 1Nal represents 1-naphthylalanine, HArg represents homoarginine, HyP represents hydroxyproline and Ci, Cii and Ciii represent first, second and third cysteine residues.”
Note that the specification should refer to U.S. Application 20190389906, rather than 2019/03889906.
The cited applications disclose a limited number of bicycle toxin conjugates specific for nectin-4 in addition to BT8009/BCY8245. Each of the bicycle toxin conjugates specific for nectin-4 that are disclosed in the cited applications appear to have the same peptide ligand region of present SEQ ID NO: 1.
The bicycle toxin conjugates specific for nectin-4 disclosed in the cited applications do not constitute a representative number of the conjugates encompassed by the present claims, comprising any peptide ligand for nectin-4, any spacer region, any cleavable linker and any toxin or having any structure that would meet the limitation of the claims of an undefined “bicycle toxin conjugate” that binds to nectin-4.
The claims define the compounds to be administered to the patients in terms of their general type and their functional effect. However, naming of a compound in terms of its functional attributes – i.e., specific for nectin-4 - is not sufficient to describe that compound. More than a statement of biological function is required to satisfy the 35 USC 112 first paragraph, written description requirement for a specific compound.
Further, naming the compound a bicycle toxin conjugate does not sufficiently describe the overall structure of the compounds that are specific for nectin-4 and which are disclosed as to be used in the claimed methods for treating cancer in a subject having a copy number of the SDHC gene greater than two.
Further, as noted in Vas-Cath Inc. v. Mahurkar (19 USPQ2d 1111, CAFC 1991), the Federal Circuit concluded that:
"...applicant must also convey, with reasonable clarity to those skilled in art, that applicant, as of filing date sought, was in possession of invention, with invention being, for purposes of "written description" inquiry, whatever is presently claimed."
Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. 112 is severable from its enablement provision.
With respect to the present invention, there is no record or description which would demonstrate conception of a representative number of bicycle toxin conjugates specific for Nectin-4. Therefore, the claims fail to meet the written description requirement because the claims encompass a potentially large genus of bicycle toxin conjugates specific for Nectin-4 which are not described in the specification.
Claim Rejections - 35 USC § 103
8. 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.
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) 51-54, 56, 60-64, 66, 69, 70 and 71 is/are rejected under 35 U.S.C. 103 as being unpatentable over Rigby, M (BT8009: A bicyclic peptide toxin conjugate targeting Nectin-4 (PVRL4) displays efficacy in preclinical tumour models. AACR Annual Meeting. May 2019, #4479; cited in the restriction requirement of 10/17/2025) in view of Riester et al (Clin Cancer Research. 2014. 29(7): 1873-1883, and Supplementary Information, 24 pages total).
Rigby teaches methods of treating a patient having a tumor that expresses Nectin-4 by administering BT8009, which is a bicycle toxin conjugate specific for nectin-4 (p.5-7). It is disclosed that nectin-4 is overexpressed in bladder, breast, pancreatic, lung and esophageal cancers (p. 4). It is further disclosed that BT8009 efficacy correlates with expression levels of nectin-4, with those tumors expressing the highest levels of nectin-4 RNA showing the highest efficacy / tumor regression (p. 9). Rigby concludes that BT8009 shows excellent efficacy in treating NSCLC, TNBC, Esophageal and bladder PDX models (p. 10).
Rigby does not teach selecting a patient to be treated with BT8009 based on the detection of a copy number of the SDHC gene of greater than 2.
However, Riester teaches that the region of 1q23 is amplified in many cancers, including bladder cancer, and that this region comprises the nectin-4 (PVRL4) gene and SDHC gene (e.g., abstract; p. 1876, col. 2 and Supplemental Table S7). It is disclosed that the copy number of the nectin4 (PVRL4) and SDHC genes correlates with the copy number of 1q23.3 and that the copy number of nectin-4(PVRL4) and SDHC correlate with their mRNA expression levels (see Supplemental Table S7 and Figures S12 and S13 for nectin-4/PVRL4). Riester (p. 1873, col. 1) teaches “gain of a short segment of chromosome 1q23.3, one of the most frequent alterations in urothelial carcinoma, was determined to confer a poor prognosis independent of known prognostic factors, and externally validated in a cohort of primary and metastatic tumors.”
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Rigby so as to have also selected patients for treatment with the BT8009 bicycle toxin conjugate specific for nectin-4 who had a copy number of SDHC greater than 2. One would have been motivated to have done so because Riester teaches that increased expression of nectin-4 correlates with increased nectin-4 copy number and that nectin-4 and SDHC show an increase in copy number in tumors, as part of the copy number gain of the 1q23.3 region. Such a modification of the method of Rigby would have provided an alternative or additional means for identifying those patients likely to express higher levels of nectin-4, and thereby more likely to respond to the bicycle toxin conjugate BT8009 and would have identified patients having a poor prognosis and most likely to be in need of treatment with BT8009.
Regarding claims 52, 54, 62 and 64, such a modification of the method of Rigby would have resulted in a method comprising measuring the copy number of SDHC in a tumor sample from a subject.
Regarding claims 53 and 63, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have selected patients having an SDHC Log2(CN ratio) of about 0.1 or more since Riester teaches that such a Log2 copy number ratio would be indicative of a gain in copy number or gene amplification (e.g., p. 2 of the Supplemental Information and the legend for figure S12 at p. 10).
Regarding claims 60 and 70, Rigby teaches that the BT8009 bicycle toxin conjugate is effective in the treatment of bladder cancer, as well as other cancers, including NSCLC, TNBC and esophageal cancer (e.g., p. 10).
Regarding claim 71, modification of the method of Rigby as set forth above would have resulted in a method comprising administering the bicycle toxin conjugate specific for Nectin-4 of BT8009 / BCY8245 to a patient wherein the patient has been selected for having a copy number of SDHC greater than 2.
9. Claims 55 and 65 are rejected under 35 U.S.C. 103 as being unpatentable over Rigby, M (BT8009: A bicyclic peptide toxin conjugate targeting
Nectin-4 (PVRL4) displays efficacy in preclinical tumour models. AACR Annual Meeting. May 2019, #4479; cited in the Office action of 10/17/2025) in view of Riester et al (Clin Cancer Research. 2014. 29(7): 1873-1883, and Supplementary Information, 24 pages total) and further in view of Morris (U.S. 20130122499).
The teachings of Rigby and Riester are presented above. The combined references do not teach that the copy number is determined by assaying a sample that comprises ctDNA.
However, Morris teaches that the copy number of a gene in a tumor cell can be detected by assaying cfDNA containing tumor DNA (i.e., ctDNA; see, e.g., para [0003-0004], [0006] and [0008]). Morris teaches that the method has numerous advantages, including “CNVs may detect cancer at an early stage of development, or cancer that may be developing in an area of the body that may not be accessible to traditional biopsy assays” (para [0116]). It is also stated that “plasma can be collected and prepared within many primary care physician offices without posing any more risk than a standard blood draw, cfDNA CNVs may be a valuable cancer biomarker” (para [0116]).
In view of the teachings of Morris, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Rigby so as to have measured the copy number of SDHC by assaying a sample from a patient with cancer comprising cfDNA (ctDNA). One would have been motivated to have done so for the benefits disclosed by Morris that the analysis of cfDNA/ctDNA in blood or plasma samples provides an easy to obtain, non-invasive (less risky) source of tumor DNA for determining copy number changes in tumor DNA.
10. Claims 58 and 68 are rejected under 35 U.S.C. 103 as being unpatentable over Rigby, M (BT8009: A bicyclic peptide toxin conjugate targeting
Nectin-4 (PVRL4) displays efficacy in preclinical tumour models. AACR Annual Meeting. May 2019, #4479; cited in the Office action of 10/17/2025) in view of Riester et al (Clin Cancer Research. 2014. 29(7): 1873-1883, and Supplementary Information, 24 pages total) and further in view of Upadhyaya, P. (Activation of CD137 using multivalent and tumour targeted bicyclic peptides. Peptide Congress, April 2019, #4479, 25 pages).
The teachings of Rigby and Riester are presented above. The combined references do not teach that the tumor cells from the subject which express Nectin-4 co-localize with CD137-expressing immune cells.
However, Upadhyaya teaches methods of treating tumors expressing nectin-4 with a bicycle toxin conjugate specific for nectin-4 (e.g., p. 4-5). It is disclosed that CD137-expressing T cells are present at tumor sites and have anti-tumor activity, and also interact with antigen presenting cells expressing CD137L (p. 8 and 13). It is also disclosed that CD137 requires clustering for activation and that “(f)ully synthetic molecules comprising CD137 and tumour antigen targeting Bicycles could achieve potent CD137 activity through receptor cross-linking across the immune synapse” (p. 15). BCY8854 is disclosed as a bispecific compound that binds to both nectin-4 and CD137 and activates T cells (p. 15, 17 and 21).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have further modified the method of Rigby so as to have administered the bicycle toxin conjugate specific for Nectin-4 to patients having tumor cells expressing nectin-4 that co-localize with CD137-expressing T cells since Upadhyaya teaches that CD137-expressing T cells are present at tumor sites and can be activated by clustering and that bispecific Nectin-4/CD137 binding agents, such as BCY8854, can be used to specifically activate the CD137-expressing T cells and thereby aid in the treatment of the tumor.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CARLA J MYERS whose telephone number is (571)272-0747. The examiner can normally be reached M-Th 6:30-5:00 EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Wu-Cheng Winston Shen can be reached on 571-272-3157. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CARLA J MYERS/Primary Examiner, Art Unit 1682