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 .
Claim Status
Claims 3-5, 8-13, 17-22, 24, 26-27, 29-32, 34, and 36-47 have been amended as requested in the preliminary amendment filed on March 14, 2024. Following the amendment, claims 1-47 are pending in the instant application.
Claims 1-47 are under examination in the instant office action.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Claims 1-47 have an effective filing date of October 2, 2020 corresponding to PRO 63/086,658.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 03/29/2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
The listing of references in 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.
Specification
The use of the terms, for example, DVD-Ig, CrossMab, Duobody, LIBTAYO, and LIPOFECTIN, which are trade names or a marks used in commerce, have been noted in this application. The terms should be accompanied by the generic terminology; furthermore the terms 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.
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 35 and 40-42 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.
The purpose of the written description requirement is to ensure that the inventor had possession, at the time the invention was made, of the specific subject matter claimed. To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116.
Claim 35 is drawn to various genera of inhibitors and/or activators (e.g., PD-L1 inhibitors, LAG-3 inhibitors, STLA-4 inhibitors, etc.). It is specifically noted that at Paragraph 119 of the instant specification, it is indicated that the inhibitors/activators of claim 35 can include antibodies, wherein a few exemplary antibodies are also provided: anti-PD-L1 antibodies as PD-L1 inhibitors, ipilimumab as a CTLA-4 inhibitor, etc. Additionally, claims 40-42 are generally drawn to the bispecific anti-CD20/CD3 antibody of claim wherein claim 40 discloses the first heavy chain, claim 41 discloses the second heavy chain, and claim 42 discloses the common light chain; however it is noted that these components are claimed separately such that no complementary heavy and light chain pairs for the first (i.e., CD20) and second (i.e., CD3) binding domains/arms are provided. However, as provided in the Examples of the instant specification (Pages 48-55), full-length bispecific anti-CD20/CD3 antibody odronextamab and full-length anti-PD-1 antibody cemiplimab are the exemplary antibodies of the method, which comprise complementary heavy and light chains in order to confer antigen binding/specificity. Even though Applicant has disclosed species of antibody inhibitors/activators and bispecific anti-CD20/CD3 antibodies with complementary heavy and light chains, Applicant is claiming large and structurally diverse genera of inhibitors/activators and bispecific antibodies, each of which could comprise antibodies and various possible heavy and light chain pairings, respectively. Absent empirical determination, one skilled in the art would be unable to immediately envision, recognize, or distinguish at least most of the members comprised within the genus claimed, specifically which antibodies for the molecules identified in claim 35 are inhibitory/activating and what heavy and light chain pairings would yield functional bispecific anti-CD20/CD3 antibodies. Accordingly, Applicant’s disclosure is not sufficient to demonstrate possession of the entire claimed genus, and Applicant’s disclosure does not satisfy the written description requirement of 35 U.S.C. 112(a).
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
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A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. As previously indicated, Applicant has species within the genera claimed. However, given the large number of species encompassed by the genera claimed as well as the high level of structure variation that would be displayed by members of the claimed genus, the disclosure of said adequately described species is not sufficiently representative of the entire genera.
Although screening techniques can be used to identify/isolate inhibitory/activating antibodies for the molecules identified in claim 35 and bispecific antibodies proteins that possess the ability to specifically bind CD20 and CD3, Applicant is reminded that the written description requirement of 35 U.S.C. 112 is severable from the enablement provision. As stated in Vas-Cath Inc. v. Mahurkar (CA FC) 19 USPQ2d 1111, 935 F2d 1555, “The purpose of the ‘written description’ requirement is broader than to merely explain how to ‘make and use’; the applicant must also 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.”
Claims 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 the treatment of patients having CD20-expressing cancers and bispecific anti-CD20/CD3 or anti-PD-1 antibodies comprising all six parental CDRs (as defined by Kabat) for each antibody and binding arm comprised therein, does not reasonably provide enablement for . 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 Breadth of the Claims
With regard to claim 1, the claim is drawn to a method of “treating or inhibiting the growth of a tumor” which further comprised selecting a subject with cancer and generally administering a bispecific anti-CD20/CD3 antibody after which an anti-PD-1 antibody is administered. As such, the claims generally read on the treatment of any and all cancer, the full scope of which is not enabled by the method as instantly claimed. Claims 2-47 are included in this rejection as they all depend from/incorporate claim 1.
With regard to claim 35, the claim recites a third therapeutic agent/therapy selected from various options, wherein said third therapeutic agent/therapy may include a cancer vaccine (see Line 2). As such, claim 35 as presented reads on cancer vaccines and prophylactic cancer treatments, the full scope of which is not enabled.
Claims 36, 38, and 44 all recite six CDR SEQ ID NOs associated with the anti-CD20 arm, anti-CD3 arm, and the anti-PD-1 antibody, respectively, utilized in the method of the claims. However, it is noted that none of the sets of six CDRs for any of the binding arms/anti-PD-1 antibody correspond to full-length CDRs as defined by Kabat. As such, the full scope of the claims is not enabled.
The State/Level of Predictability in the Prior Art
Cancer treatment is highly unpredictable. Even though the EGFR was identified in some cancers as a drug target, the in vitro (i.e., in a test tube) effectiveness of a drug in inhibiting the EGFR turned out to be a poor proxy for how effective that drug actually was in treating cancer in vivo (i.e., in the body). Numerous EGFR inhibitors that showed promising in vitro activity failed for a variety of reasons. These included poor pharmacokinetics due to poor absorption or rapid metabolism ( [**2]or both), undesirable drug-drug interactions, drug toxicity due to drug binding onto healthy cells, drug toxicity due to binding onto other receptors, and metabolite toxicity. Some drug candidates were limited by one or more of these shortcomings, further underscoring the unpredictable nature of cancer treatment. OSI Pharmaceuticals , LLc, v. Apotex Inc, 939 F.3d 1375, 2019.
The state of the art at the time of filing was such that the functionality of an anti-tumor antibody was dependent on both its action on the intended target and whether or not the modulation of said target had an effect on any particular cancer cell. Baxevanis (Expert Opinion: Drug Discovery, Vol. 3, No. 4, Pg. 441-452, 2008) teaches that, depending on the epitope against which an antibody is directed, antibody-antigen binding may neutralize circulating targets or cell surface receptors (Pg. 444, Column 1, Paragraph, first full). They teach that presently available monoclonal antibodies (mAbs) are directed against molecular targets that are expressed on tumor cells or play an important role in the tumor microenvironment (Pg. 444, Column 1, Paragraph, first full; Table 1). Table 1 lists currently available antibodies for use in clinical oncology and illustrates that each antibody has a specific target (Table 1, Column 2) and a specific set of cancers for which it has therapeutic utility (Table 1, Column 4). Taken together, the art does not recognize a single antibody that is an effective therapy against all tumors.
To further illustrate this point, Baxevanis goes on to explain the functionality of the more commonly used therapeutic antibodies. Trastuzumab targets the receptor HER-2 (HER-2/neu) which is overexpressed in some breast cancers and so is a viable treatment for said breast cancers (Pg. 444, Column 2, Lines 19-24). The basis of this variability in treatment response is due to the fact that the growth inhibitory effect of anti-HER-2 is dependent on the extent of HER-2 overexpression (pg. 443, Column 1, Paragraph, first partial). Because only a portion of breast cancer patients overexpress HER-2 and respond to trastuzumab, the selection of suitable patients is important (Pg. 445, Column 1, Lines 13-15).
Rituximab is an antibody against CD20 antigen, which is expressed on most B cells including B-cell lymphomas (Pg. 445, Column 1, Lines 36-38). Therefore, it is used to treat B-cell lymphomas (Pg. 444, Table 1). It has been used to treat patients with relapsed or refractory low-grade non-Hodgkin's lymphoma (a B-cell lymphoma) (Pg. 445, Column 1, Lines 41-50).
In contrast to trastuzumab and rituximab, some therapeutic antibodies show efficacy in treating multiple cancers. This stems from the fact that their target antigen is associated with multiple cancers. Cetuximab is an anti-EGFR antibody (Pg. 445, Column 1, Lines 19-20). EGFR is overexpressed in many epithelial cell tumors (Pg. 445, Column 1, Lines 20-21). The association of EGFR overexpression with multiple cell types gives cetuximab a broader therapeutic applicability than trastuzumab (Pg. 444, Table 1) as it is used to treat both renal and head and neck cancers.
As a final point, the art also recognizes that the function of the therapeutic antibody must correlate with an effect on its target conducive to tumor growth inhibition or tumor lysis, resulting in patient benefit. Anti-HER-2 antibodies, like Trastuzumab, disrupt HER-2 catalytic activity (Pg. 443, Column 1, Paragraph, first partial, Sentence, ultimate; Table 1, Column 3, (S) referring to decreased protein signaling (activity); and Pg. 444, Column 2, Lines 19-22). Cetuximab also inhibits its target’s activity as it prevents EGFR dimerization and subsequent activation via phosphorylation (Pg. 445, Column 1, Lines 23-25). Since both HER-2 and EGFR activity support growth of cancer cells in which they are overexpressed, their inhibition is therapeutic to patients. Rituximab causes tumor cell lysis by antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) (Pg. 445, Column 1, Lines 38-39) and so its therapeutic benefit is provided by specifically inducing cancer cell death.
The teachings of Baxevanis discussed above underline the requirement of a link between an inhibitory antibody’s target and specific cancers to make therapy of said cancer predictable to one of ordinary skill in the art.
With regard to cancer vaccines/cancer prevention, no material has been found to date that has been shown to or would be expected to prevent cancer. Reasonable guidance with respect to preventing any cancer relies on quantitative analysis from defined populations that have been successfully pre-screened and are predisposed to particular types of cancer. This type of data might be derived from widespread genetic analysis, cancer clusters, or family histories. The essential element towards the validation of a preventive therapeutic is the ability to test the drug on subjects monitored in advance of clinical cancer and link those results with subsequent histological confirmation of the presence or absence of disease. This irrefutable link between antecedent drug and subsequent knowledge of the prevention of the disease is the essence of a valid preventive agent. Further, a preventive administration also must assume that the therapeutic will be safe and tolerable for anyone susceptible to the disease.
The vaccine art teaches that compositions comprising some tumor associated antigens are effective in treatment of cancer through generation of immunogenic response to the tumor antigen (see for example, Komenaka et Al., Clinics in Dermatology, 2004, Vol. 22, Pg. 251-265, specifically page 257). However, nowhere in the art does it show that tumor antigens are effective at preventing cancer. Evans et Al. (Q. J. Med 1999: 92: 299-307) teach that vaccines against cancer are not fully established, and it is stated that adjuvant therapy to prevent or delay disease still needs experimentation. Evans et Al. further state that such cancer vaccines are at best used as a therapeutic and not as a prophylactic and that “the notion that cancer vaccines will replace standard therapeutic strategies in malignant disease still belongs to the realm of fiction” (see page 303 last paragraph).
In some cases, it is known that certain cancers arise from a single cause. This cause can be viral as in the case of cervical cancer, caused predominantly by persistent cervical infection with human papillomavirus (HPV) (Schiffman et Al., The New England Journal of Medicine, Vo. 353, No. 20, Pg. 2101-2104, 2005). Schiffman et Al. teach that primary prevention through vaccination against HPV might be possible in young women (Pg. 2101, Column 3, Paragraph, first parital). However, they also teach that vaccine evaluations are ongoing (Pg. 2103, Column 3, Paragraph, first full). In addition, the most promising vaccines designed against HPV types 16 and 18 would only prevent 70 percent of cervical cancer cases at best (Pg. 2103, Column 2, Paragraph, first full). Therefore, there is still no vaccine that can definitively prevent a cancer. Current evidence points only to the potential of future prophylactic agents.
With regard to antibodies, the state of the prior art is such that it is well established in the art that the formation of an intact antigen-binding site of antibodies generally requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs or hypervariable regions, which provide the majority of the contact residues for the binding of the antibody to its target epitope (Paul, Fundamental Immunology, 3rd Edition, 1993, pp. 292-295, under the heading “Fv Structure and Diversity in Three Dimensions”). The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity, which is characteristic of the immunoglobulin. It is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites (Paul, page 293, first column, lines 3-8 and line 31 to column 2, line 9 and lines 27-30).
Additionally, Bendig M. M. (Methods: A Companion to Methods in Enzymology, 1995; 8:83-93) reviews that the general strategy for “humanizing” antibodies involves the substitution of all six CDRs from a rodent antibody that binds an antigen of interest, and that all six CDRs are involved in antigen binding (see entire document, but especially Figures 1-3). It is noted that Bendig used Kabat CDRs in their humanization process (Pg. 86, Column 2, Paragraph, second; emphasis added). Similarly, the skilled artisan recognized a “chimeric” antibody to be an antibody in which both the heavy chain variable region (which comprises the three heavy chain CDRs) and the light chain variable region (which comprises the three light chain CDRs) of a rodent antibody are recombined with constant region sequences from a human antibody of a desired isotype (see entire document, but especially Figures 1-3).
Thus, the state of the art recognized that it would be highly unpredictable that a specific antibody comprising less than all six parental CDRs (as defined by Kabat) would have antigen binding function. The minimal structure which the skilled artisan would consider predictive of the function of binding the antigen of a murine or humanized antibody includes six CDRs (three from the heavy chain variable region and three from the light chain variable region) in the context of framework sequences which maintain their correct spatial orientation and have the requisite binding function.
In the case of antibodies, it is especially important to disclose which residues are permissive to mutation. Even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function as evidenced by Rudikoff et al. (Proceedings of the National Academy of Sciences USA, Vol., 79, Pg. 1979-1983, 1982). Rudikoff et al. teach that the alteration of a single amino acid in the CDR of a phosphocholine-binding myeloma protein resulted in the loss of antigen-binding function.
Johnson and Wu (Methods in Molecular Biology, Antibody Engineering: Methods and Protocols, Vol. 248, Pg. 11-25, 2004) teach that complete CDRs of antibodies CDRH1-3 and CDRL1-3 are at least 5, 16, 8, 11, 7, and 9 amino acid residues in length respectively (Pg. 12, Paragraph, second full). In instant claim 7, CDRH2 has 8 residues, CDRL1 has 6 residues and CDRL2 has 3 residues. These are significantly smaller than the CDR lengths of Kabat CDRs and so would not be expected to confer antigen binding to an antibody framework barring evidence to the contrary. They amount to no more than mutated Kabat CDRs. It is noted that the CDRs of claim 7 were not used to humanize the 4C11 antibody. All humanized variants of 4C11 comprise Kabat CDRs such as those in claim 8 (Table 1). Thus, claim 7 and its dependents that recite only CDRs do not recite a complete set of CDRs known to confer antigen binding to a framework and amount to mutated Kabat CDRs. Mutated CDRs would not predictably bind antigen. Even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function as evidenced by Rudikoff et al. (Proc Natl Acad Sci USA 79: 1979-1983, 1982). Rudikoff et al. teach that the alteration of a single amino acid in the CDR of a phosphocholine-binding myeloma protein resulted in the loss of antigen-binding function.
Therefore, even antibodies comprising the CDRs of claims 36, 38, and/or 44 are not enabled. Barring experimental evidence, such mutated and truncated CDRs would be insufficient to confer antigen binding function.
In view of the above, one of skill in the art would neither expect nor predict the appropriate functioning of the antibody fragments and antibodies of the instant claims, comprising mutated/shortened Kabat CDRs, as broadly as claimed because CDR mutation makes antigen binding unpredictable as is established in the art; it has not been demonstrated that CDRs shorter than those defined by Kabat (i.e., mutated Kabat CDRs) predictably function and bind target antigen in the humanization process.
The Amount of Direction Provided by the Inventor/Existence of Working Examples
Applicant has provided no working examples regarding cancer vaccines and the prevention/prophylactic treatment of cancer.
The working Examples provided by Applicant (Pages 48-55 of the specification) are all drawn to full-length bispecific anti-CD20/CD3 antibody odronextamab and full-length anti-PD-1 antibody cemiplimab; said antibodies must comprise all six full-length CDRs as defined by Kabat, but the instant claims are drawn to antibodies that comprise shortened/mutated Kabat CDRs. Furthermore, these working Examples utilize CD20+ tumor cells (e.g., WSU-DLCL2 cells, which is a human B-cell lymphoma cell line) or utilize models/simulations based on B-NHL.
In view of the lack of the predictability of the art to which the invention pertains as evidenced by the art above, the lack of guidance and direction provided by Applicant, and the absence of working examples, undue experimentation would be required to make and use functional antibodies comprising fewer than all six full-length parental CDRs (as defined by Kabat) with a reasonable expectation of success, absent a specific and detailed description in Applicant’s specification of how to effectively practice this and absent working examples providing evidence which is reasonably predictive that the claimed antibodies are functional, commensurate in scope with the claimed invention.
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 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.
With regard to claim 1, the claim recites a bispecific antibody that comprises an arm that specifically binds CD3 and an arm that specifically binds CD20. No structural relationship between the two moieties is provided by claim 1. This gives claims 1-47 multiple interpretations. The first is that the anti-CD3 arm is covalently linked to the anti-CD20 arm. The second is that the two are not covalently associated at all and instead are simply in the same solution as an oligoclonal antibody. As such, the broadest reasonable interpretation of the instant claims’ “bispecific antibody” includes both a single molecule with two binding moieties, and a biclonal/oligoclonal antibody. The presence of two very different structural interpretations of the instant claims renders them indefinite.
With regard to claims 4, 6-9, 15-18, the term “about” is a relative term which renders the claim indefinite. The term “about” is not defined by the claims, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. It is noted that .
With regard to claim 23, it is unclear as to if the limitation of “the subject has cytokine release syndrome” refers to the subject having CRS before the method of claim 1 or if the patient has CRS after step (b) of the method of claim 1. As such, the claim is considered to be indefinite.
With regard to claims 26-28, it is unclear as to if the limitation of “the subject is resistant to, inadequately responsive to, or relapsed after prior therapy” refers to the subject being resistant/inadequately responsive/relapsed to a therapy prior to steps (a)-(b) of the method of claim 1 or if the patient becomes resistant/inadequately responsive/relapsed prior to after step (b) and before step (c). As such, the claims are considered to be indefinite.
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.
Claim 23 is 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. Claim 23 fails to further limit the method of claim 1 from which it depends; claim 23 recites the method of claim 1 wherein the subject has CRS, however claim 1 recites that the method of claim 1 ameliorates CRS which indicates that the subject must have CRS. Therefore claim 23 is not considered to be further limiting. 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 Interpretation
It is specifically noted that the preamble of the instant method claims, drawn to intended uses, and the wherein clauses comprised therein, drawn to intended results, do not give patentable weight to the claims.
If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, then the preamble is not considered a limitation and is of no significance to claim construction. Shoes by Firebug LLC v. Stride Rite Children’s Grp., LLC, 962 F.3d 1362, 2020 USPQ2d 10701 (Fed. Cir. 2020) (The court found that the preamble in one patent’s claim is limiting but is not in a related patent); Pitney Bowes, Inc. v. Hewlett-Packard Co., 182 F.3d 1298, 1305, 51 USPQ2d 1161, 1165 (Fed. Cir. 1999). See MPEP 2111.02(II). Furthermore, claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure. The court noted that a "‘whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’" Id. (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)). See MPEP 2111.04.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1-3, 5, 22, 24-39, and 44-47 is/are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by US 2017/0174779 A1 (herein after referred to as "Varghese").
With regard to claims 1-2, Varghese teaches methods for treating, reducing the severity, or inhibiting the growth of cancer (e.g., a B-cell cancer such as Hodgkin's lymphoma or acute lymphoblastic leukemia) wherein the methods of the invention comprise administering to a subject in need thereof a therapeutically effective amount of an antibody or antigen-binding fragment thereof that specifically binds to programmed death 1 (PD-1) receptor in combination with a therapeutically effective amount of a bispecific antibody that specifically binds to CD20 and CD3 (Abstract). The expression “a subject in need thereof” means a human or non-human mammal that exhibits one or more symptoms or indications of cancer, and/or who has been diagnosed with cancer, including a B-cell cancer, and who needs treatment for the same; the expression also includes patients with a B-cell cancer that is resistant to or refractory to or is inadequately controlled by prior therapy (e.g., treatment with a conventional anti-cancer agent), and therefore “a subject in need thereof” includes a patient that has cancer (Paragraph 0035). The expression “in combination with” means that the anti-CD20/anti-CD3 bispecific antibody is administered before, after, or concurrent with the anti-PD-1 antibody; the term “in combination with” also includes sequential or concomitant administration of anti-PD-1 antibody and a bispecific anti-CD20/anti-CD3 antibody (Paragraph 0073; emphasis added). When administered “after” the bispecific anti-CD20/anti-CD3 antibody, the anti-PD-1 antibody may be administered about 10 minutes, about 15 minutes, about 30 minutes, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 60 hours, about 72 hours, or more than 72 hours after the administration of the bispecific anti-CD20/anti-CD3 antibody (Id.). The phrase "therapeutically effective amount" means an amount of antibody (anti-PD-1 antibody or bispecific anti-CD20/CD3 antibody) that results in one or more of: (a) a reduction in the severity or duration of a symptom of a B-cell cancer; (b) inhibition of tumor growth, or an increase in tumor necrosis, tumor shrinkage and/or tumor disappearance; (c) delay in tumor growth; (d) inhibit or retard or stop tumor metastasis; (e) prevention of recurrence of tumor growth; (f) increase in survival of a subject with a B-cell cancer; and/or (g) a reduction in the use or need for conventional anti-cancer therapy (e.g., reduced or eliminated use of chemotherapeutic or cytotoxic agents) as compared to an untreated subject or a subject administered with either antibody as monotherapy (Paragraph 0093). In certain embodiments, each dose of the anti-CD20/anti-CD3 antibody is administered in more than one fractions, e.g., in 2-5 fractions ("split dosing") within the given dosing period; the anti-CD20/anti-CD3 bispecific antibody may be administered in split doses to reduce or eliminate the cytokine "spikes" induced in response to administration of the antibody wherein cytokine spikes refer to the clinical symptoms of the cytokine release syndrome ("cytokine storm") and infusion related reactions, seen in patients administered anti-CD20 antibodies (Paragraph 0039). Thus, Varghese teaches methods of treating cancer comprising administering, to a patient having cancer, a therapeutically effective amount of a bispecific anti-CD20/CD3 antibody and an anti-PD-1 antibody, wherein said anti-PD-1 antibody may be administered after the bispecific antibody and wherein the bispecific antibody is administered in split doses to reduce or eliminate cytokine spikes. Varghese teaches the active steps od claims 1-2, and as such it is noted that the intended result of treating or inhibiting the growth of a tumor and ameliorating CRS will necessarily occur. As such Varghese anticipates claims 1-2.
With regard to claims 3 and 5, Varghese teaches that the expression “in combination with” means that the anti-CD20/anti-CD3 bispecific antibody is administered before, after, or concurrent with the anti-PD-1 antibody; the term “in combination with” also includes sequential or concomitant administration of anti-PD-1 antibody and a bispecific anti-CD20/anti-CD3 antibody (Paragraph 0073; emphasis added); multiple doses of an anti-PD-1 antibody in combination with a bispecific anti-CD20/anti-CD3 antibody may be administered to a subject over a defined time course (Paragraph 0085).As such, Varghese anticipates claims 3 and 5.
With regard to claim 22, Varghese teaches methods which comprise administering an anti-PD-1 antibody in combination with a bispecific anti-CD20/CD3 antibody to a subject wherein the antibodies are contained within separate or combined (single) pharmaceutical composition; methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes (Paragraphs 0078-0079). Thus, Varghese anticipates claim 22.
With regard to claims 24-25, Varghese teaches that in certain embodiments, the cancer or tumor is a heme cell tumor or malignancy or the cancer or tumor is a B-cell tumor wherein the B-cell tumor is selected from the group consisting of Hodgkin's lymphoma, non-Hodgkin's lymphoma, follicular lymphoma, small lymphocytic lymphoma, lymphoplasmacytoid lymphoma, marginal zone lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, B-cell lymphomas, lymphomatoid granulomatosis, Burkitt's lymphoma, acute lymphoblastic leukemia, hairy cell leukemia, and B cell chronic lymphocytic leukemia (Paragraph 0010). Thus, Varghese anticipates claims 24-25.
With regard to claims 26-28, Varghese teaches methods for treating, reducing the severity, or inhibiting the growth of cancer (e.g., a B-cell cancer such as Hodgkin's lymphoma or acute lymphoblastic leukemia) wherein the methods of the invention comprise administering to a subject in need thereof a therapeutically effective amount of an antibody or antigen-binding fragment thereof that specifically binds to programmed death 1 (PD-1) receptor in combination with a therapeutically effective amount of a bispecific antibody that specifically binds to CD20 and CD3 (Abstract). The expression “a subject in need thereof” means a human or non-human mammal that exhibits one or more symptoms or indications of cancer, and/or who has been diagnosed with cancer, including a B-cell cancer, and who needs treatment for the same; the expression also includes patients with a B-cell cancer that is resistant to or refractory to or is inadequately controlled by prior therapy (e.g., treatment with a conventional anti-cancer agent), including subjects who have previously been treated with a CD20 inhibitor (e.g., rituximab, and anti-CD20 antibody)(Paragraph 0035). Thus, Varghese anticipates claims 26-28.
With regard to claims 29-33, the intended results disclosed in the claims will necessarily occur. Furthermore, it is noted that Varghese teaches methods for treating, reducing the severity, or inhibiting the growth of cancer (e.g., a B-cell cancer such as Hodgkin's lymphoma or acute lymphoblastic leukemia) wherein the methods of the invention comprise administering to a subject in need thereof a therapeutically effective amount of an antibody or antigen-binding fragment thereof that specifically binds to programmed death 1 (PD-1) receptor in combination with a therapeutically effective amount of a bispecific antibody that specifically binds to CD20 and CD3 (Abstract). The phrase "therapeutically effective amount" means an amount of antibody (anti-PD-1 antibody or bispecific anti-CD20/CD3 antibody) that results in one or more of: (a) a reduction in the severity or duration of a symptom of a B-cell cancer; (b) inhibition of tumor growth, or an increase in tumor necrosis, tumor shrinkage and/or tumor disappearance; (c) delay in tumor growth; (d) inhibit or retard or stop tumor metastasis; (e) prevention of recurrence of tumor growth; (f) increase in survival of a subject with a B-cell cancer; and/or (g) a reduction in the use or need for conventional anti-cancer therapy (e.g., reduced or eliminated use of chemotherapeutic or cytotoxic agents) as compared to an untreated subject or a subject administered with either antibody as monotherapy (Paragraph 0093). More specifically, Varghese teaches increased inhibition of tumor growth by 10-80% compared to an untreated subject or subject administered with either antibody as a monotherapy and/or a delay in tumor growth by 3+ days, 1+ months, and/or 3+ years compared to an untreated subject or subject administered with either antibody as a monotherapy (Paragraph 0047). Thus, Varghese anticipates claims 29-33.
With regard to claims 34-35, Varghese further teaches that the methods of the invention can further comprise administration of a third therapeutic agent selected from the group including, for example, radiation, surgery, a cancer vaccine, a PD-Ll inhibitor (e.g., an anti-PD-Ll antibody), a LAG-3 inhibitor, a CTLA-4 inhibitor (e.g., ipilimumab ), a TIM3 inhibitor, a BTLA inhibitor, a TIGIT inhibitor, a CD47 inhibitor, etc. (Paragraph 0075). Thus, Varghese anticipates claims 34-35.
With regard to claims 36-39, Varghese teaches exemplary bispecific anti-CD20/anti-CD3 antibody used in the Examples ("bsAbl" which is also known as "Antibody 1" as disclosed in US 2015/0266966, i.e., “Smith”), a fully human bispecific monoclonal antibody against CD20 and CD3 wherein the antibody comprises an anti-CD20 binding arm comprising a first heavy chain variable region (A-HCVR) comprising the amino acid sequence of SEQ ID NO: 11 and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 12; and an anti-CD3 binding arm comprising a second heavy chain variable region (B-HCVR) comprising the amino acid sequence of SEQ ID NO: 13 and a LCVR comprising the amino acid sequence of SEQ ID NO: 12. It is specifically noted that Varghese SEQ ID NOs: 11-13 are 100% matches to instant SEQ ID NOs: 11-13, respectively, and comprise 100% matches to instant SEQ ID NOs: 14-19 (heavy chain CDR1-3 and light chain CDR1-3 of anti-CD20 arm) and SEQ ID NOs: 17-22 (light chain CDR1-3 and heavy chain CDR1-3 of anti-CD3 arm). Thus, Varghese anticipates claims 36-39.
With regard to claims 44-47, Varghese teaches an exemplary antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10; this exemplary antibody is the fully human anti-PD-1 antibody known as REGN2810 (Paragraph 0058). It is specifically noted that Varghese SEQ ID NOs: 9 and 10 are 100% matches to instant SEQ ID NOs: 9 and 10, respectively. As such, Varghese SEQ ID NO: 9 comprises 100% matches to instant SEQ ID NOs: 3-8 (corresponding to heavy chain CDR1-3 and light chain CDR1-3) and 1-2 (corresponding to the heavy chain variable and light chain variable regions). It is specifically noted that REGN2810 is known in the art as cemiplimab. Thus, Varghese anticipates claims 44-47.
Claim Rejections - 35 USC § 103
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.
As disclosed under the Claim Interpretation section above, the method claim preambles and/or wherein clauses, relating to intended uses and intended results, are not given patentable weight. However, even if the preambles and wherein clauses were given weight, they do not distinguish the methods from the prior art below.
Claim(s) 1-35 and 44-47 is/are rejected under 35 U.S.C. 103 as being unpatentable over US 2017/0174779 A1 (herein after referred to as "Varghese") in view of non-patent literature by Hosseini et. al. (npj Systems Biology and Applications, August 2020, 6(28); herein after referred to as "Hosseini").
With regard to claims 1-2, Varghese teaches methods for treating, reducing the severity, or inhibiting the growth of cancer (e.g., a B-cell cancer such as Hodgkin's lymphoma or acute lymphoblastic leukemia) wherein the methods of the invention comprise administering to a subject in need thereof a therapeutically effective amount of an antibody or antigen-binding fragment thereof that specifically binds to programmed death 1 (PD-1) receptor in combination with a therapeutically effective amount of a bispecific antibody that specifically binds to CD20 and CD3 (Abstract). The expression “a subject in need thereof” means a human or non-human mammal that exhibits one or more symptoms or indications of cancer, and/or who has been diagnosed with cancer, including a B-cell cancer, and who needs treatment for the same; the expression also includes patients with a B-cell cancer that is resistant to or refractory to or is inadequately controlled by prior therapy (e.g., treatment with a conventional anti-cancer agent), and therefore “a subject in need thereof” includes a patient that has cancer (Paragraph 0035). The expression “in combination with” means that the anti-CD20/anti-CD3 bispecific antibody is administered before, after, or concurrent with the anti-PD-1 antibody; the term “in combination with” also includes sequential or concomitant administration of anti-PD-1 antibody and a bispecific anti-CD20/anti-CD3 antibody (Paragraph 0073; emphasis added). When administered “after” the bispecific anti-CD20/anti-CD3 antibody, the anti-PD-1 antibody may be administered about 10 minutes, about 15 minutes, about 30 minutes, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 60 hours, about 72 hours, or more than 72 hours after the administration of the bispecific anti-CD20/anti-CD3 antibody (Id.). The phrase "therapeutically effective amount" means an amount of antibody (anti-PD-1 antibody or bispecific anti-CD20/CD3 antibody) that results in one or more of: (a) a reduction in the severity or duration of a symptom of a B-cell cancer; (b) inhibition of tumor growth, or an increase in tumor necrosis, tumor shrinkage and/or tumor disappearance; (c) delay in tumor growth; (d) inhibit or retard or stop tumor metastasis; (e) prevention of recurrence of tumor growth; (f) increase in survival of a subject with a B-cell cancer; and/or (g) a reduction in the use or need for conventional anti-cancer therapy (e.g., reduced or eliminated use of chemotherapeutic or cytotoxic agents) as compared to an untreated subject or a subject administered with either antibody as monotherapy (Paragraph 0093). In certain embodiments, each dose of the anti-CD20/anti-CD3 antibody is administered in more than one fractions, e.g., in 2-5 fractions ("split dosing") within the given dosing period; the anti-CD20/anti-CD3 bispecific antibody may be administered in split doses to reduce or eliminate the cytokine "spikes" induced in response to administration of the antibody wherein cytokine spikes refer to the clinical symptoms of the cytokine release syndrome ("cytokine storm") and infusion related reactions, seen in patients administered anti-CD20 antibodies (Paragraph 0039). Thus, Varghese teaches/suggests methods of treating cancer comprising administering, to a patient having cancer, a therapeutically effective amount of a bispecific anti-CD20/CD3 antibody and an anti-PD-1 antibody, wherein said anti-PD-1 antibody may be administered after the bispecific antibody and wherein the bispecific antibody is administered in split doses to reduce or eliminate cytokine spikes.
Hosseini teaches that mosunetuzumab, a T-cell dependent bispecific antibody that binds CD3 and CD20 to drive T-cell mediated B-cell killing, is currently being tested in non-Hodgkin lymphoma, but potent immune stimulation with T-cell directed therapies poses the ri