DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
This office action is in response to an amendment filed 10/7/2025.
Claims 2-24 are under examination.
This application claims priority as a 371 filing of PCT/US2021/036540 filed 6/9/2021 which claims priority to U.S. provisional 63/036,740 filed 6/9/2020.
Response to Amendments
The amendments are sufficient to overcome the objections to the claims.
Claim Objections
Claim 23 is objected to because of the following informalities: claim 23 depends from a cancelled claim.
Claim Rejections - 35 USC § 112, second paragraph
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 23 recites the limitation "the antibody" in claim 1. There is insufficient antecedent basis for this limitation in the claim. Claim 1 is cancelled.
Claim Rejections - 35 USC § 112 ¶4 rejection
The following is a quotation of the fourth paragraph of 35 U.S.C. 112:
Subject to the [fifth paragraph of 35 U.S.C. 112 prohibiting improper multiple dependent claims], 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.
Claim 10 is rejected under 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. Claim 10 now depends from claim 2. Therefore, as amended, the claim requires that the antibody which I s no longer a variant is “an antibody fragment” which does not encompass the totality of claim 2, 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. This is a new rejection necessitated by applicants’ amendment.
Claim Rejections - 35 USC § 112, first paragraph
The following is a quotation of the first paragraph of 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 20 and 22-24 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for a method of treating a tumor expressing hNTSR1 in a subject comprising thereof with an antibody wherein the antibody comprises: heavy chain CDR1: GYTFTSSWIH (SEQ ID NO: 3) or GYAFTSSWIH (SEQ ID NO: 4); heavy chain CDR2: QIRPNSGNTY YNEKFKV (SEQ ID NO: 5); heavy chain CDR3: ARYYYGFDY (SEQ ID NO: 6), ARYHYGFDY (SEQ ID NO: 7), or ARYRYGEFDY (SEQ ID NO: 8); light chain CDR1: RSSQSIVHSNGNTYLE (SEQ ID NO: 9); light chain CDR2: KVSNRES (SEQ ID NO: 10); and light chain CDR3: FQGSHLPWT (SEQ ID NO: 11) or FOGAHLPWT (SEQ ID NO: 12) or a method of detecting hNTSR1 comprising contacting a sample, tissue or cell with the antibody and detecting binding, does not reasonably provide enablement for any other embodiment. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims. This rejection is maintained for reasons of record.
The test of enablement is whether one skilled in the art could make and use the claimed invention from the disclosures in the patent coupled with information known in the art without undue experimentation (United States v. Telectronics, Inc., 8 USPQ2d 1217 (Fed. Cir. 1988)). Whether undue experimentation is required is not based on a single factor but is rather a conclusion reached by weighing many factors (See Ex parte Forman, 230 USPQ 546 (Bd. Pat. App. & Inter, 1986) and In re Wands, 8USPQ2d 1400 (Fed. Cir. 1988); these factors include the following:
1) Nature of invention. The instant claims are drawn to immunotherapy and diagnostic methods using an antibody.
2) Scope of the invention. The scope of the invention is fairly broad in that the method of treating is to any subject regardless of tumor/non-tumor status wherein the broadly recited antibody as set forth above is administered.
3) Number of working examples and guidance. The specification is directed to discovery of anti-hNTSR1 antibodies and three variants were tested in vivo. These variants were h7C3-3, h7C3-4 and h7C3-5 comprising the combinations of sequences including heavy chain CDR1: GYTFTSSWIH (SEQ ID NO: 3) or GYAFTSSWIH (SEQ ID NO: 4); heavy chain CDR2: QIRPNSGNTY YNEKFKV (SEQ ID NO: 5); heavy chain CDR3: ARYYYGFDY (SEQ ID NO: 6), ARYHYGFDY (SEQ ID NO: 7), or ARYRYGEFDY (SEQ ID NO: 8); light chain CDR1: RSSQSIVHSNGNTYLE (SEQ ID NO: 9); light chain CDR2: KVSNRES (SEQ ID NO: 10); and light chain CDR3: FQGSHLPWT (SEQ ID NO: 11) or FOGAHLPWT (SEQ ID NO: 12). These antibodies were conjugated with cancer drug monomethyl auristin E (MMAE). These antibodies showed efficacy in mouse models.
[0099] Nude mice were subcutaneously inoculated with NTSR1-expressing cells, H1299 (1×10.sup.6 cells per mouse). When the tumors reached a volume of 200 mm.sup.3, the tumor-bearing mice were grouped (n=6) and administered intravenously with human IgG (negative control), h7C3-3-MMAE, h7C3-4 and h7C3-4-MMAE, respectively, at 10 mg/Kg twice weekly for six doses. The Cisplatin (positive control) was administered intravenously at 7 mg/Kg weekly for three doses. As shown in FIG. 11A, 10 mg/kg of h7C3-4-MMAE inhibited the tumor growth more potently than the control human IgG (10 mg/kg) and Cisplatin (7 mg/kg) groups on day 18. Prolonged regression of tumor was observed in h7C3-4-MMAE treatment until 35 days compared with Cisplatin, a positive control commonly used in clinical therapeutic treatments for non-small cell lung cancer. Furthermore, 10 mg/kg of h7C3-3-MMAE showed partial inhibition of the tumor growth on day 35, indicating that h7C3-4 was internalized more efficiently than h7C3-3 in lung xenograft model.
[0100] To compare the anti-tumor efficacies of h7C3-3-MMAE and h7C3-4 MMAE, an experiment was performed with 5×10.sup.6 HA22T-luc liver cancer cells inoculated subcutaneously to SCID mice. Tumor-bearing mice were divided into 3 groups (n=8). When the tumors reached a volume of 200 mm.sup.3, 10 mg/Kg of human IgG, h7C3-3-MMAE and h7C3-4 MMAE were administered intravenously, respectively, twice weekly for four doses. Both h7C3-3-MMAE and h7C3-4 MMAE showed tumor regression on day 15 (FIG. 12A), and prolonged regression of tumor were observed in both ADC treatments until 36 days.
4) State of the art. The art of antibody design is set forth above. As to NTSR1, Nikolaou teaches that neurotensin functions through its receptor both with endocrine and neuromodulator activity. It has three receptors NTSR1, 2 and 3. NTSR1 is comprised of 424 amino acids and is a high affinity receptor.
Preliminary studies have shown NT and its receptors to promote cell proliferation, DNA synthesis, migration and angiogenesis through autocrine and paracrine effects in many cancers (Fig. 2). Their direct effect on MAPK pathway, EGFR transactivation and Protein kinase C and D pathway activation makes them an interesting target in therapeutic use in the subset of cancers which express NT and/or its receptors, making way for a promising new tumour agnostic drug. They also show potential as prognostic and predictive markers. Although there is promise in the use of these markers in animal models, further study is required to assess its applicability in clinical use (Table 1).
5) Unpredictability of the art. Administering the antibody of the invention even if limited to any subject regardless of their status suggests therapy for those at risk. Therefore, the claim as drawn to prevention is very unpredictable. In humans, the claimed diseases are usually established before therapy is offered. The specification does not adequately teach how to effectively predict for whom prevention would be required. One establishes a large genus of target subjects for whom the method is intended, however, establishing whether a person or persons actually requires the treatment is a highly unpredictable art. Screening procedures for indications of those requiring inhibition of the onset of disease are unknown and highly prejudicial leading to conditions in which those who require the treatment cannot be distinguished from those who do not. In this case, applicants exacerbate the unpredictability of the art by reciting subjects to be targeted for whom the disease must be prevented.
6) Amount of Experimentation Required. In view of the unpredictability of the art of predicting the ability to treat without the ability to predict for whom the therapies exist and given the large breadth of antibodies used in the therapy and detection: undue experimentation would be required to practice the claimed methods with reasonable expectation of success, absent a specific and detailed description in the specification. Given the unpredictability of the art, the poorly developed state of the art with regard to predicting the subjects for therapy as well as structure function of the antibodies, the lack of adequate working examples and the lack of guidance provided by applicants, the skilled artisan would have to have conducted undue, unpredictable experimentation to practice the claimed invention.
Response to Applicant’s arguments
Applicants argue that because the claims now depend from claim 2, they overcome the rejection. However, this is not the full basis of the rejection. The tumor, tissue or sample should be one that comprises hNTSR1 without which the method will not perform as necessary. Hence, the subject in need thereof must be a subject with a tumor comprising hNTSR1. As well, claim 23 has not been amended to overcome previous issues.
Double Patenting
A rejection based on double patenting of the "same invention" type finds its support in the language of 35 U.S.C. 101 which states that "whoever invents or discovers any new and useful process ... may obtain a patent therefor ..." (Emphasis added). Thus, the term "same invention," in this context, means an invention drawn to identical subject matter. See Miller v. Eagle Mfg. Co., 151 U.S. 186 (1894); In re Ockert, 245 F.2d 467, 114 USPQ 330 (CCPA 1957); and In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970).
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the "right to exclude" granted by a patent and to prevent possible harassment by multiple assignees. See In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970);and, In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) may be used to overcome an actual or provisional rejection based on a nonstatutory double patenting ground provided the conflicting application or patent is shown to be commonly owned with this application. See 37 CFR 1.130(b).
Effective January 1, 1994, a registered attorney or agent of record may sign a terminal disclaimer. A terminal disclaimer signed by the assignee must fully comply with 37 CFR 3.73(b).
Claims 2 and 9-24 are rejected under the judicially created doctrine of non-statutory double patenting as being unpatentable over claims 1-19 of U.S. Patent 12,091,454. This rejection is maintained for reasons of record.
An obviousness-type double patenting rejection is appropriate where the conflicting claims are not identical, but an examined application claim is not patentably distinct from the reference claims because the examined claim is either anticipated by, or would have been obvious over, the reference claims. Although the conflicting claims are not identical, they are not patentably distinct from each other because the cited claims of the instant invention are generic to all that is recited in claims 1-19 of U.S. Patent 12,091,454. That is, the cited claims of U.S. Patent 12,091,454 anticipate and fall entirely within the scope of the rejected claims of the instant application. Specifically, application U.S. Patent 12,091,454 is drawn to overlapping antibodies as well as methods of use. The overlap is shown below.
RAI 1- result#13 84.8% US-18-089-812 SEQ ID NO:13
Alignment statistics for match #1
Score
Expect
Method
Identities
Positives
Gaps
211 bits(537)
1e-77
Compositional matrix adjust.
101/112(90%)
107/112(95%)
0/112(0%)
Query 1 DVLMTQTPLSLPVSLGDQASISCRSSQSIVHSNGNTYLEWYLQKPGQSPKLLIYKVSNRF 60
D++MTQTPLSL V+ G ASISCRSSQSIVHSNGNTYLEWYLQKPGQSP+LLIYKVSNRF
Sbjct 1 DIVMTQTPLSLSVTPGQPASISCRSSQSIVHSNGNTYLEWYLQKPGQSPQLLIYKVSNRF 60
Query 61 SGVPDRFSGSGSGTDFTLKISRVEAEDLGVYYCFQGSHLPWTFGGGTKLEIK 112
SGVPDRFSGSGSGTDFTLKISRVEAED+GVYYCFQGSHLPWTFG GTK+EIK
Sbjct 61 SGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHLPWTFGQGTKVEIK 112
RAI 3 #4 60 100.0 116 US-18-089-812-13 \
RAI 5 #4 93 100.0 116 US-18-089-812-13
RAI 6 #2 55 100.0 116 US-18-089-812-13
SEQ ID NO:s 9, 10 and 11 are shown in SEQ ID NO:12 below.
DIVMTQTPLSLSVTPGQPASISCRSSQSIVHSNGNTYLEWYLQKPGQSPQLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHLPWTFGQGTKVEIK
Additionally, if a patent resulting from the instant claims was issued and transferred to an assignee different from the assignee holding the U.S. Patent 12,091,454, then two different assignees would hold a patent to the claimed invention of U.S. Patent 12,091,454, and thus improperly there would be possible harassment by multiple assignees.
Response to Arguments
Applicants argue that the copending patent has a later filing date and based upon their review of cases with this fact pattern would make moot this rejection in this application. However, PTAB cases are not precedential. Rather, the question to be addressed according to the current standard when addressing a double patenting rejection based upon a patent is are the conflicting claims similar or the same. This does not seem to be in contest.
Conclusion
Claims 3-8 are dependent on rejected claims but would be allowable if redrafted in independent form.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARIA MARVICH whose telephone number is (571)272-0774. The examiner can normally be reached 8 am - 5 pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Maria Leavitt can be reached at 571-272-1085. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/MARIA MARVICH/Primary Examiner, Art Unit 1634