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 .
Information Disclosure Statement
The listing of references at the end 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, they have not been considered.
Foreign references 1-4 in the Information Disclosure Statement filed 6/2/2025 fail to comply with 37 CFR 1.98(a)(3)(i) because they do not include a concise explanation of the relevance, as it is presently understood by the individual designated in 37 CFR 1.56(c) most knowledgeable about the content of the information, of each reference listed that is not in the English language. As a result, the information referred to therein has not been considered.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," 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 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) 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") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) 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 of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency - The Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is missing or incomplete. See item 1) a) or 1) b) above.
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.
Specification
Abstract
Applicant is reminded of the proper content of an abstract of the disclosure.
A patent abstract is a concise statement of the technical disclosure of the patent and should include that which is new in the art to which the invention pertains. The abstract should not refer to purported merits or speculative applications of the invention and should not compare the invention with the prior art.
See MPEP § 608.01(b) for guidelines for the preparation of patent abstracts.
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided.
The Abstract refers to purported merits by reciting, “Also disclosed is the advantageous use….” The instant Abstract recites, “The disclosure relates to”.
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01. See Bibliography on pages 46-47 of specification. It is suggested that “https://” be deleted.
The disclosure is objected to because of the following informalities: On p. 35, line 14, it appears the second occurrence of “OX40” should perhaps be “CD40L”. On p. 46, line 4, “Sandrine” should apparently be deleted after “Immunotherapy”.
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, 6, 8, 16 and 21 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 5 and 6 are indefinite because they recite, ”the OX40 agonist antibody comprises a heavy and/or light chain of an OX40 agonist IgG antibody or an antigen-binding fragment thereof.” It is unclear if the “antigen-binding fragment” is of the OX40 agonist IgG or the OX40 agonist antibody comprising a heavy and/or light chain of an OX40 agonist IgG.
Claim 8 is confusing because in line 2 it recites “one or more antigens” and line 3 recites “the antigen-binding fragment thereof”. It is unclear if the one or more antigens is necessarily OX40 or can be any antigen. Dependent claim 9 further limits the antigen but does clarify claim 8 by itself.
Claim 10 is indefinite because it is contradictory. It depends from claim 1 which requires an OX40 binding domain of OX40L. Claim 10 also recites a formula comprising OX40L; however, the claim ends with “OX40L is the binding domain of the ligand of OX40 comprising SEQ ID NO:2 and is absent when x is 1 or is a bond.” The claims require OX40L. It cannot be absent. If it is, claim 10 would not further limit claim 1 and would be contrary to the preamble.
Claim 16 is indefinite because it recites “said T cells are … cytokines.” As T cells are not cytokines, it appears a phrase such as “cytokines secreted by” was intended to appear before “T cells”.
Claim 21 is indefinite because it recites “eliciting cell proliferation and/or inducing cytokine proliferation of T cells”. First, it is unclear of which cells proliferation is elicited, e.g., is it any cells or T cells. Second, cytokines do not proliferate. For the second issue, it may have been intended to recite ‘cytokine production by’ or ‘cytokine-induced proliferation of’ T cells.
Claim Rejections - 35 USC § 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.
Claim 7 is 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 7 is drawn to an OX40 activating protein comprising at least an OX40 agonist antibody or antigen-binding fragment thereof and the OX40 binding domain of OX40L wherein according to section (c) is an antibody that competes for binding to OX40 expressing cells with an antibody identified in (a) or (b) of the claim, i.e., respectively an antibody having the heavy chain variable region (VH) CDR1-3 of SEQ ID NO:3-5 and light chain variable region (VL) CDR1-3 of SEQ ID NO:6-8 or the VH of SEQ ID NO:9 and VL of SEQ ID NO:10. The prior art teaches an OX40 antibody having the above VH and VL CDR1-3 (see instant specification on p. 11, line 21, and US Patent 9,738,723 B2). While US Patent 9,738,723 teaches the approximate epitope of the antibody (col. 5, lines 31-39), the claims are not drawn to an antibody binding the same epitope, but to a competing antibody which is only required to compete with the disclosed antibody and not necessarily bind the same epitope. It must also be an OX40 agonist. This is a huge genus of antibodies of which a single antibody is disclosed.
As stated by Ladner (Biotechnol. Genet. Eng. Rev. 24:1-30, 2007, p. 3) in the section on "Competitive Binding to the Ag", "This method can show that two Abs bind to overlapping or to non-overlapping epitopes, but not that they bind to the same epitope." (emphasis added by author) The specification discloses a single OX40 agonist antibody and none that compete therewith. Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111 (Fed. Cir. 1991), clearly states that “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).
With the exception of an antibody comprising the VH and VL CDR1-3 referred to above, the skilled artisan cannot envision the detailed chemical structure of the encompassed competing antibodies, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016 (Fed. Cir. 1991).
One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483 (BPAI 1993). In Fiddes, claims directed to mammalian FGF's were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence. In this case, the claims are directed to any antibody that is an OX40 agonist and competes with and antibody having at least the above described VH and VL CDRs, while the specification provides no other antibody sequence with the required functions.
Therefore, only the OX40 agonist antibody selected from (a), (b) or (d) of claim 7, but not the full breadth of the claim meets the written description provision of 35 U.S.C. § 112(a). 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 (see page 1115).
Claims 10, 18 and 19 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 10 is drawn to an OX40 activating protein comprising a light chain formula αOX40Light-PL1-OX40L and a heavy chain of the formula αOX40Heavy-(PL2-Ag)x, wherein Ag is one or more viral and/or cancer antigens and x is 0 or an integer from 1-20. Dependent claim 18 further defines the linkers. Dependent claim 19 limits x to 1-5. Structurally, the activating protein requires an antibody heavy and light chain. The specification has shown only a construct where x=0 to have biological properties (Example 2). Figure 1 is a schematic of the claimed antibody construct where x=1. Neither the specification nor the prior art supports a genus of OX 40 activating proteins having a structure meeting the formula requirements where x is greater than 1. The size of an antibody structure affects its function. For example, Xenaki et al. (Front. Immunol. 8:1287, 2017) discusses antibodies and their application in imaging and targeted therapy (note the use of the instant antibody is described in the specification as an in vitro assay tool to look T at cell cytokine production and proliferation and, primarily, an in vivo immune effector, e.g., p.39, lines 18-20 and p. 1, lines 5-6). For treatment or imaging of tumors, Xenaki et al. states (paragraph bridging pp. 2-3) that a targeting antibody or antigen-binding fragment thereof needs to cross the vascular wall of the tumor blood vessels to reach tumor cells. “Properties of both the targeting macromolecule (e.g., size, shape, and charge) and the vessel wall (e.g., pore size) can influence vascular permeability…” Larger size can enhance permeability and retention (EPR) of the macromolecule in solid tumors, but “Together, both increased IFP [interstitial fluid pressure] and abnormal vasculature (leading to non-homogenous distribution of larger molecules within the tumor) counteract the benefits of the EPR effect.” (p. 3, col. 1, first and second paragraphs). Further, it has been shown that diffusion through extracellular matrix of IgGs is slower for larger molecules (p. 3, col. 2, first full paragraph). While IgG-containing proteins have longer half-lives that increase therapeutic index, if the molecule has low accessibility to the target site, the longer half-life may not be sufficient for activity to occur (p. 4, last paragraph). Not only does the instant antibody have an immunoglobulin structure, i.e., having a heavy and light chain of an antibody, it has a OX40L linked to the C-terminus of each light chain and an antigen(s) linked to the C-terminus of the heavy chain, making this molecule significantly larger than native immunoglobulins. The claimed protein must have the property of activating OX40. With the limited teachings in the specification and warnings about antibody size in the prior art, it does not appear the inventors were in possession of the claimed invention where x is greater than 1.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111 (Fed. Cir. 1991), clearly states that “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).
Therefore, only an OX40 activating protein comprising a light chain formula αOX40Light-PL1-OX40L and a heavy chain of the formula αOX40Heavy-(PL2-Ag)x, wherein x is 0 or 1, but not the full breadth of the claim meets the written description provision of 35 U.S.C. § 112(a). 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 (see page 1115).
Claim 20 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the OX40 activating protein of claim 1, does not reasonably provide enablement for prevention of cancer. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The claimed method is drawn to preventing cancer. However, in order to be able to prevent cancer, one must first be able to anticipate its onset and second be able to maintain administration throughout the duration of susceptibility or produce an immune response so cancer does not occur. While the instant OX40 activating protein of claim 1 reasonably appears to be able to stimulate a T cell-mediated immune response, there is no working example of or direction or guidance to allow the skilled artisan to reasonably expect that such a response would be sufficient for prevention of cancer. The term “preventing” generally carries the meaning of keeping something from happening. The immunomodulator effect that OX40/OX40L activation has is dependent on activation of the OX40 pathway, which is not activated without stimulation, suggesting that prevention with the protein of claim 1 would require if not continuous, at least frequent administration of the protein. However again, there is no information in the specification about administration frequency or dosage to accomplish this, let alone about how to anticipate when such administration would need to begin. While the protein would reasonably be expected to boost immune response for the treatment of cancer (see, e.g., Fu et al., Acta Pharmaceutical Sinica B, 10(3):414-433, 2020, p. 424, last paragraph of col. 1 and first of col. 2), prevention has completely different requirements. Treatment of cancer is complex. The protein of claim 1 targets T cells and not particular cancers. Fu et al. (ibid., p. 424, col. 2, first paragraph) discusses that, “[P]oorly immunogenic tumors my not provide the priming required by OX40-OX40L signals.” This supports the potential unpredictability of OX40 agonist effect on certain cancers. It would require undue experimentation to practice the method commensurate in scope with the claim as it relates to prevention.
Claims 2, 15, 21 and 22 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 for i) a method for eliciting cell proliferation of CD4+ and CD8+ T cells and/or inducing cytokine production by CD4+ and CD8+ T cells and ii) a method of boosting T cell-mediated immunity against cancer cells in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the OX40 activating protein of claim 1, does not reasonably provide enablement for eliciting cell proliferation of cells other than CD4+ and CD8+ T cells and/or inducing cytokine production by other than CD4+ and CD8+ T cells or boosting immunity against cancer cells that is not T cell-mediated. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The claims are drawn to an OX40 activating protein comprising at least an OX40 agonist antibody or antigen-binding fragment thereof and the OX40 binding domain of OX40L. Claim 2 is drawn to the OX40 activating protein of claim 1 which i) “induces the proliferation of T cells, as measured in vitro by flow cytometric analysis…” There is no limitation related to the types of T cells induced to proliferate. Dependent claim 15 only has limitations drawn to the flow cytometric analysis. Independent claim 21 is drawn to a method for eliciting cell proliferation and/or inducing cytokine proliferation of T cells. The claim is unclear as to whether cell proliferation is of T cells (see rejection under 35 USC 112(b) above). The claim also does not limit the type of T cells. Further for claim 21, it reasonably appears Applicant intended not ‘inducing cytokine proliferation of T cells’ but ‘cytokine production by T cells’ as supported in instant Fig. 4 and on p. 39, lines 18-23. As stated by Fu et al., (Acta Pharmaceutical Sinica B, 10(3):414-433, 2020, p. 424, last paragraph of col. 1), “Many studies have demonstrated the rationale of targeting OX40-OX40L interactions in cancer immunotherapy, as ligation of OX40 signals can promote conventional (non-regulatory) CD4+ and CD8+ T cell survival, sustain anti-apoptotic protein expression like BCL-XL, BCL-2 and survivn, enhance cytokine production like IL-2, IL-4, IL-5 and IFN-γ, boost effector tumor-specific T cell immune responses, and augment tumor-specific memory T cell generation following antigen challenge, as summarized in Fig. 34,10,11.” There is no working example, guidance or direction, nor support in the prior art to reasonably expect cytokine-induced proliferation of T cells by activation of OX40. Independent claim 22 is drawn to boosting immunity against cancer cells. There is no limitation as to the type of immunity being boosted (e.g., B cell or T cell).
Additionally, both the specification and prior art support the ability of OX40 to boost T cell-mediated immunity against cancer cells and proliferation of CD4+ and CD8+ T cells, but not other cells. The specification teaches that in vitro an OX40 activating protein of claim 1 evoked proliferation of primed human CD4+ T cells (p. 39, lines 18-20, see also, e.g., Fu et al., supra, p. 420, col., 2, last full paragraph). Linch et al. (Front. Oncol. 5:34, 15 pages, 2015, p. 1, paragraph bridging cols. 1-2) teaches that OX40 is expressed by CD4+ and CD8+ T cells during antigen-specific priming, though this expression is largely transient (see also instant specification, p. 1, lines 8-11). There are no working examples of direct OX40 activation effects on immune cells other than T cells, particularly CD4+ and CD8+ T cells. Immunity is an extremely complex web of interactions of a vast array of proteins and cells. OX40 binds only OX40L. While other proteins may interact with its effect, they do not directly interact with OX40 (e.g., CTLA-4 inhibition combined with an OX40 agonist has been shown to significantly enhance survival in mouse models of several cancers, Linch et al., supra, Table 1).
Because of the reasons discussed above and including the lack of working examples for an effect (proliferation, induction of cytokine production or other immune response) on any cells as required other than CD4+ and CD8+ T cells, the prior art teaching of OX40 expression on and activation of CD4+ and CD8+ T cells without significant effect on other immune cells, the lack of guidance or direction in the specification to provide the skilled artisan with a reasonable expectation of effect on other immune cells, the breadth of the claims, and the complexity of immune responses, it would require undue experimentation to practice the methods commensurate in scope with the claims.
Allowable Subject Matter
Claims 9 and 17 would be allowable if rewritten to overcome the rejection(s) under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), 2nd paragraph, set forth in this Office action and to include all of the limitations of the base claim and any intervening claims.
Claims 1, 3, 4 and 11 are allowed.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Claire Kaufman, whose telephone number is (571) 272-0873. Examiner Kaufman can generally be reached Monday through Friday 7am-3:30pm, Eastern Time.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Vanessa Ford, can be reached at (571) 272-0857.
Any inquiry of a general nature or relating to the status of this application should be directed to the Group receptionist whose telephone number is (571) 272-1600.
Official papers filed by fax should be directed to (571) 273-8300. NOTE: If applicant does submit a paper by fax, the original signed copy should be retained by the applicant or applicant's representative. NO DUPLICATE COPIES SHOULD BE SUBMITTED so as to avoid the processing of duplicate papers in the Office.
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 .
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free).
Claire Kaufman
/Claire Kaufman/
Primary Examiner, Art Unit 1674
August 8, 2025