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 .
DETAILED ACTION
Claims 1-9, and 12-20 are pending and under consideration.
It is noted that prior art does not teach or suggest neutralizing anti-CD95L monoclonal antibody having the CDR1L-CDR2L-CDR3L and CDR1H-CDR2H-CDR3H as recited by claim 1.. In addition, the methods of treatment (claims 12-18 and 20) are not enabled by the instant specification and prior art. see 112(a) rejections in detail.
Priority
It is acknowledged that this application is a 371 of International Application No. PCT/EP2022/083881 filed November 30, 2022, which claims the benefit of priority to Foreign Patent Appl. No. EP21306672.3 filed December 1, 2021.
Certified copies of foreign priority applications have been received as required by 37 CFR 1.55.
Thus, priority date has been established as December 1, 2021 for the pending claims.
Information Disclosure Statement
The Information Disclosure Statement filed on 05/13/2024 has been considered and entered by examiner.
Specification
The disclosure is objected to because of the following informalities: The current application was filed after July 1, 2022, thus the WIPO Standard ST.26, Sequence Listing in XML format, applies to sequence disclosures. See 37 CFR § 1.831. An ST.26 Sequence Listing in XML must not include any sequences having fewer than 10 specifically defined nucleotides, or fewer than 4 specifically defined amino acids. See 37 CFR § 1.831(j).
The specification filed 05/13/2024 refers to SEQ ID NO: 4 (e.g. page 11, line 24). These sequences are replaced with “000” in the Sequence Listing in XML because the sequence is less than 4 amino acid sequence. SEQ ID NO: 4 in the specification should be deleted and replaced with “NTF” because the Sequence Listing in XML does not contain the short sequence.
The disclosure is objected to because of the following informalities: the specification describes the antibody having the VL domain as set forth in SEQ ID NO: 1 and the VH domain as set forth in SEQ ID NO: 5, e.g. at the bridging paragraph of pages 9-10; the 2nd paragraph of page 12. However, SEQ ID NO: 1 and SEQ ID NO: 5 are not VL and VH domains. Based on the specification, SEQ ID NO: 2 and SEQ ID NO: 6 are the correct VL and VH domains, respectively.
Appropriate correction is required.
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter “Legal Framework”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation by reference statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
Specific deficiency - The incorporation by reference paragraph required by 37 CFR 1.834(c)(1), 1.835(a)(2), or 1.835(b)(2) is missing, defective or incomplete.
Required response - Applicant must:
• Provide a substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required incorporation by reference paragraph, consisting of:
• A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
• A copy of the amended specification without markings (clean version); and
• A statement that the substitute specification contains no new matter.
Claim Objections
Claim 1 is objected to because of the following informalities: “the CDR2L having the amino acid sequence NTF (SEQ ID NO: 4)” should be replaced by “the CDR2L having the amino acid sequence NTF”. SEQ ID NO: 4 appears as “000” (skipped sequence) within the Sequence Listing, but based on the specification, SEQ ID NO: 4 refers to the sequence NTF.
Claim 16 is objected to because of the following informalities: “and” on the bottom line of page 5 should be deleted.
Claim 16 is objected to because of the following informalities: “or” in “or monoclonal” on line 13 of page 6 should be deleted.
Claim 16 is objected to because of the following informalities: “and” on line 9 of page 8 should be deleted.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 5 and 16 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 5 recites “conservative sequence modification” which renders the claim indefinite. The claim does not teach the structure of the VH and VL domains that are being modified thus, it is unclear what modifications can be considered as conservative.
Regarding claim 16, the phrase "bronchiolitis obliterans (non-transplant) vs NSIP” on page 6 renders the claim indefinite because: 1) it is unclear whether the limitation in the parenthesis is part of the claimed invention; 2) it is unclear whether NSIP is encompassed by reciting “vs NSIP”. See MPEP § 2173.05(d).
Regarding claim 16, the phrase "such as" on line 10 page 6 renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claim 16, the phrase "such as" on line 21 page 7 renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claim 16, the phrase "such as" on the bottom line of page 7 renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
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 12-18 and 20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The specification discloses an anti-CD95L monoclonal antibody: JQ3 which can neutralize CD95-CD95L signaling in Jurkat cells and CD95-mediated Ca2+ response in neutrophils isolated different donors (health, COVID19, or AAV). However, the claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention. This is an Enablement rejection.
To be enabling, the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1561 (Fed. Cir.,1993). Explaining what is meant by "undue experimentation," the Federal Circuit has stated that:
The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which experimentation should proceed to enable the determination of how to practice a desired embodiment of the claimed invention. PPG v. Guardian, 75 F.3d 1558, 1564 (Fed. Cir. 1996).
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth by In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 wherein, citing Ex parte Forman, 230 USPQ 546 (Bd. Apls. 1986) at 547, the court recited eight factors to consider when assessing whether or not a disclosure would require undue experimentation. These factors are:
1) the quantity of experimentation necessary, 2) the amount of direction or guidance provided, 3) the presence or absence of working examples, 4) the nature of the invention 5) the state of the art, 6) the relative skill of those in the art, 7) the predictability of the art and 8) the breadth of the claims.
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099, 1108,427 F.2d 833, 839, 166 USPQ 18, 24 (1970). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
Nature of invention and breadth of the claims:
The claims are drawn to a method of treating a broad genus of cancers (unlimited cancers, including triple negative breast cancer), and treating a broad genus of inflammatory diseases (at least including hundreds of diseases listed in claim 16).
In addition, as set forth above, the claims also encompass an enormous number of antibody variants which may or may not have the required therapeutic activities.
Relative skill in the art:
The relative skill of those in the art is high with an MD or a PhD.
Level of unpredictability in the art and State of the prior art:
The cancer therapy art is generally unpredictable, requiring each embodiment to be individually assessed for physiological activity. The instant claim read on diagnosis and treatment of a broad genus of cancers. Gerdes et al. (Front. Oncol. 12/18/2014 doi: 10.3389/fonc.2014.00366, pp. 1-12, of record) teach that cancer is a multifaceted disease characterized by heterogeneous genetic alterations, cellular metabolism at the organ, tissue, and cellular levels and these conditions vary between cancers. See abstract and Fig. 1. Gerdes et al. teach that the tumor microenvironment is a highly heterogeneous mix of cellular and non-cellular components and can promote or be antagonistic to tumor growth. See Tumor Microenvironment-Heterogeneity and Anticancer Therapeutic Target-pages 5-6 and Fig. 1. Similarly, different inflammatory diseases are caused by different signaling pathways (see Figs. 3-9 of Bansal et al., RPS Pharmacy and Pharmacology Reports, 2023, 2, 1-11, Publication Date: 03/31/2023).
Regarding up to all possible variations encompassed by the claims, it is well known that in the variable domain of an antibody, even outside the CDRs, can significantly impact antibody binding. Mutations in the framework regions (non-CDR areas) can alter the structure and dynamics of the antibody, affecting its ability to bind to its target antigen. For example, even single amino acid change in antigen-distal framework position can result in different conformational space and potentially different binding functions, see § Significance on page E486 of Koenig (Koenig et al., PNAS, E486-E495, Publication Date: 01/05/2017).
In addition, for CD95L, Zhang (Zhang et al., Frontiers in Immunology, 13:1029737, Publication Date: 11/24/2022) teaches that other than cancers, CD95L is also expressed by other types of cells, such as endothelial cells, polymorphonuclear myeloid-derived suppressor cells, cancer-associated fibroblasts, and tumor associated microglia, and macrophages, which are educated by the tumor microenvironment and can induce apoptosis of tumor-infiltrating lymphocytes, which recognize and kill cancer cells. The dual role of the CD95-CD95L system makes targeted therapy strategies against CD95 or CD95L in glioblastoma difficult and controversial (the whole document, e.g. Abstract). Risso (Risso et al., Cell Death and Disease (2022) 13:248, Publication Date: 03/17/2022) teaches CD95L-induced cell death has multiple roles in the immune response since it constitutes one of the mechanisms by which cytotoxic lymphocytes kill their targets, but it is also involved in the process of turning off the immune response. Furthermore, beyond the canonical pro-death signals, CD95L, which can be membrane-bound or soluble, also induces non-apoptotic signaling that contributes to its tumor-promoting and pro-inflammatory roles (Abstract of Risso).
Taken together, the therapeutic activity of a neutralizing anti-CD95L antibody (e.g. JQ3 or its variants) is unpredictable and requires clinical testing.
Direction or guidance and working examples:
MPEP § 608.01 (p) provided that within the specification, "specific operative embodiments or examples of the invention must be set forth. Examples and description should be of sufficient scope to justify the scope of the claims. The instant specification shows one specific antibody: discloses an anti-CD95L monoclonal antibody: JQ3 which can neutralize CD95-CD95L signaling in Jurkat cells and CD95-mediated Ca2+ response in neutrophils isolated different donors (health, COVID19, or AAV), in cell assays in vitro. The instant specification does not offer any working examples for any antibody encompassed by the claims for treating any disease encompassed by the claims.
The quantity of experimentation needed:
The factors outlined in In Re Wands' mentioned above apply here, and in particular as per the MPEP 2164.01 (a): "A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)." It is very clear that one could not make/use this very broad invention that has no working examples in this unpredictable art without undue experimentation. Genentech Inc vs Nova Nordisk 42 USPQ 2d 1001 "A patent is not a hunting license. It is not a reward for search but compensation for its successful conclusion and patent 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."
In order to treat all encompassed diseases with all encompassed antibodies (and variants), a considerable amount of experimentation is needed given the unpredictability of the function of antibodies and targeted diseases.
Due to the large quantity of experimentation necessary to test the use of claimed compositions to treat various diseases (including all cancers and all inflammatory diseases); the lack of direction/guidance presented in the specification regarding which structural features are required in order to provide activity; the state of the prior art which establishes the unpredictability of the antibody and cancer therapy; and the breadth of the claims, undue experimentation would be required of the skilled artisan to use the claimed invention in its full scope.
Related Prior Art
Gieffers (Gieffer et al., WO 2017/051002, Publication Date: 03/30/2017, cited in IDS of 05/13/2024) teaches an anti-CD95L monoclonal antibody characterized in that the antibody specifically binds to an epitope of human CD95L comprising the amino acid sequence RNSKYP (claim 1). Gieffers teaches specific sequences for the antibody (claims 5-8, and 10-16). Gieffers teaches antibodies that can neutralize CD95 binding to CD95L (Example 7). Thus, Gieffers teaches neutralizing anti-CD95L monoclonal antibody with different CDRs. Given the unpredictability in the art, one of ordinary skill in the art would not be able to reach the antibodies as instantly claimed.
Pincelli (Pincelli et al., US 2011/0038867 A1, Publication Date: 02/17/2011, cited in IDS of 05/13/2024) teaches antibodies directed against human Fas ligands (also named CD95L) (Abstract). Pincelli teaches the CDRs of specific anti-CD95L monoclonal antibodies ([0054-0066]). Pincelli teaches the antibodies have neutralizing activity ([0080]). Thus, Pincelli teaches neutralizing anti-CD95L monoclonal antibody with different CDRs. Given the unpredictability in the art, one of ordinary skill in the art would not be able to reach the antibodies as instantly claimed.
Conclusion
Claims 5, 12-18 and 20 are rejected.
Claim 1 is objected.
Claims 2-4, 6-9, and 19 are objected because they are dependent on the objected claims directly or indirectly. However, claims 2-4, 6-9, and 19 would be allowable if claim 1 is appropriately amended.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHENG LU whose telephone number is (571)272-0334. The examiner can normally be reached Monday-Friday 8-5.
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/CHENG LU/ Examiner, Art Unit 1642
/PETER J REDDIG/ Primary Examiner, Art Unit 1646
