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, 4, 14-16, 22, 23, 29-30, 32, 34-36, and 39-42 are pending.
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. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 120 as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. PRO 63/190,466 fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application.
The claim limitations of claim 1 “administering to the patient an effective amount of an antibody or antibody fragment which binds to glycosylated CEACAM5 and CEACAM6” and the limitations of claim 4(i)-(iv), claim 14(i)-(v) were introduced in Application PCT/US2022/030028, thereby priority date for these limitations is 5/19/2022.
Specification/Abstract
The abstract of the disclosure is objected to because it states “e.g.” A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
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 title of the invention is not descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed.
The following title is suggested: METHODS AND COMPOSITIONS FOR TREATING HEMATOLOGICAL MALIGNANCIES COMPRSING ADMINISTERING AN ANTIBODY AGAINST GLYSOCYLATED CEACAM5 AND CEACAM6.
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: This application contains sequence disclosures in accordance with the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.831(a) and 1.831(b). However, this application fails to comply with the requirements of 37 CFR 1.831-1.834. The Examiner has noted that Figures 12 and 14 4 do not have SEQ ID Nos for the recited sequences.
Applicant must provide:
• A replacement “Sequence Listing XML” part of the disclosure, as described above in item 1. or 2., as well as
• A statement that identifies the location of all additions, deletions, or replacements of sequence information in the “Sequence Listing XML” as required by 1.835(b)(3);
• A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.835(b)(4);
• A statement that the “Sequence Listing XML” includes no new matter in accordance with 1.835(b)(5); and
• A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required incorporation by reference paragraph as required by 37 CFR 1.835(b)(2), consisting of:
o A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
o A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Claim Objections
Claims 4 and 14 are objected to because of the following informalities: Claim 4 refers to Figures 11 and 19 in (i)-(iii) and Figure 5 in (iv) and claim 14 refers to figures 11 and 19 in (ii)-(iv) and figure 5 in (v). However, the claims should recite the relevant material from these figures in the claims for clarity. MPEP 2173.05(s) states: “Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table “is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience.” Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993) (citations omitted). Reference characters corresponding to elements recited in the detailed description and the drawings may be used in conjunction with the recitation of the same element or group of elements in the claims. See MPEP § 608.01(m).” Appropriate correction is required.
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 1, 4, 14-16, 22, 23, 29-30, 32, 34-36, and 39-42 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. This is a WRITTEN DESCRIPTION rejection.
The claims are drawn to a method of treating or preventing a hematological malignancy and/or decreasing the burden of a hematological malignancy, or slowing the growth or proliferation rate of a hematological malignancy and/or killing malignant hematological cells in a patient in need thereof, comprising administering to the patient an effective amount of an antibody or antibody fragment which binds to glycosylated CEACAM5 and CEACAM6 but not to aglycosylated CEACAM5 or aglycosylated CEACAM6, optionally wherein the antibody is NEO- 201 or an antibody comprising the same CDRs as NEO-201. Claim 34 recites a method of killing a hematological malignant cells in vitro, comprising contacting said hematological malignancy cells with a NEO-201 antibody.
Claim 15 recites the following: (vii) and (viii) that the antibody comprises a heavy chain sequence having at least 90% (or 95%) identity to amino acids 20-470 of SEQ ID NO: 28 and a light chain sequence having at least 90% (or 95%) identity to amino acids 20-233 of SEQ ID NO: 29; (xv) is comprised in a chimeric antigen receptor (CAR); (xvi) is a multispecific or bispecific antibody which targets at least one other antigen. Claim 16 recites that the antibody is administered as an immune cell which expresses said antibody, such as a CAR comprising said antibody. Claim 30 recites that the other agent is administered with the antibody is an anti-cancer vaccine.
Thus, the written description is directed to the following:
The claims encompass a vast genus of antibodies that bind to glycosylated CEACAM5 and CEACAM6 but not to aglycosylated CEACAM 5 or CEACAM5, optionally where the antibody is NEO-201, or comprises the same CDR’s as NEO-201 (Claim 1)
The partial structure of the NEO-201 antibody, wherein the sequences can have a little more than 10% sequence discrepancy from the instantly claimed CDRs (Claim 15)
That the antibody is a multispecific or bispecific antibody, or a CAR, thus providing partial structure of the antibody. (Claim 15)
Claim 34 encompasses a vast genus of sequence variants of an “NEO-201 antibody”. The claim does not recite the structure of the NEO-201 antibody, only the function as recited above.
Cancer vaccine as noted in claim 30
The instant specification discloses only a single exemplary species of a NEO-201 antibody that comprises heavy and light chain variable region SEQ IDs NOs 28 and 29, or heavy and light chain SEQ ID NOs 38 and 39, or all six CDR SEQ ID NOs 32-37, and function as claimed. [72,] The specification fails to disclose any other structural sequences required of the claimed antibody to possess the function of treating cancer. The instant specification does not disclose any multispecific or bispecific antibodies, nor any CAR-T cells comprising the instantly claimed antibodies. The instant specification does not disclose any representative variants of the antibody with less than 100% SEQ ID Nos.
With regards to antibodies that bind to glycosylated CEACAM5 and CEACAM6 but not to aglycosylated CEACAM5 and CEACAM6, as well as the “NEO-201 antibody”, the claims encompass a vast genus of antibodies. The structure activity relationship of the CDR antigen binding regions that recognizes NEO-201 is not known and the binding epitopes cannot be predicted based on the antibody sequences as demonstrated by the prior art: Sato et al (Generation of a monoclonal antibody recognizing the CEACAM glycan structure and inhibiting adhesion using cancer tissue-originated spheroid as an antigen. Sci Rep. 2016 Apr 21;6:24823) teaches methods of generating an antibody that recognizes CEACAM glycan structures and teaches one example of an antibody, 5G2 monoclonal antibody, and teaches that the major antigens of the antibody was CEACAM5 and CEACAM6. [pg 5 and 6] Sato also teaches that the antibody could be a more tumor-specific marker and further analysis is required, and that although one antibody was studies, due to the ability of antibodies to internalize is critical for antibody-mediated targeting and further screening by may be usefl for further antibody-mediated drug candidates. [pg 11] With regards to the NEO-201 antibody that’s listed as an example of the antibody that binds to glycosylated CEACAM 5 and 6, Fantini et al (Preclinical Characterization of a Novel Monoclonal Antibody NEO-201 for the Treatment of Human Carcinomas. Front Immunol. 2018 Jan 4;8:1899) teaches that NEO-201 is a novel humanized IgG1 monoclonal antibody and found to be reactive against human carcinoma cell lines. The art teaches that this is a novel agent that warrants clinical testing as a therapeutic agent. [see whole document]
Additionally, by the time of the filing of the instant application, it was well established in the art that the formation of an intact antigen-binding site in an antibody usually required the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three “complementarity determining regions” (“CDRs”) which provide the majority of the contact residues for the binding of the antibody to its target epitope. E.g., Almagro & Fransson, Frontiers in Bioscience 2008; 13:1619-33; (see Section 3 “Antibody Structure and the Antigen Binding Site” and Figure 1). Humanized antibodies comprise only the CDRs, or in some cases an abbreviated subset of residues within the CDRs, of a parental rodent antibody in the context of human framework sequences. Id. at Section 4. All of the CDRs of the heavy and light chain, in their proper order of CDR1, then 2, then 3, and in the context of framework sequences which maintain their required conformation are generally required to produce a humanized antibody in which the heavy and light chains associate to form an antigen-binding region that binds the same antigen as the parental rodent antibody. Id. at Section 4.
Antibody binding to the same antigen, or even the same epitope on that antigen, can be accomplished with an impressively wide variety of antibody structures, even when the antibodies are limited to those from a particular source (Gershoni et al., Epitope Mapping, Biodrugs 2007; 21 (3): 145-156 page 146 section 1.1). The skilled artisan therefore understood that antibodies from a variety of different sources may bind the same antigen and even mediate the same functional effects, but differ widely in the details of the structure of their antigen-binding sites, particularly in the amino acid sequence and length of VH-CDR3.
Further, it is not possible to predict the amino acid sequence when an epitope is recited, because there are many different epitope arrangements, such as linear and discontinuous epitopes that is dictated by the unique interaction between an antibody and its cognate epitope (Blythe et al., Benchmarking B cell epitope prediction: Underperformance of existing methods, Protein Science (2005), 14:246–248 pg. 246) . 3D structural analyses of antibody-epitope binding highlighting that the deficiency in the ability to predict the structural features of an antibody when the epitope is disclosed (Schreiber et al.,3D-Epitope-Explorer (3DEX): Localization of Conformational Epitopes within Three-Dimensional Structures of Proteins, Wiley Interscience, 2005 42–44, 60596, page 879).
With regards to the partial structures of the antibody: changes in amino acid structures, particularly in CDR regions, can have impacts on antigen binding that are unpredictable. Rabia et al (Understanding and overcoming trade-offs between antibody affinity, specificity, stability and solubility. Biochemical engineering journal, 137, 365–374, 2018) and Vajdos et al (Comprehensive functional maps of the antigen-binding site of an anti-ErbB2 antibody obtained with shotgun scanning mutagenesis. Journal of molecular biology, 320(2), 415–428, 2022) teaches that changes to CDRs are unpredictable in terms of affinity, specificity, and solubility, (see Rabia whole documents), and teaches that even minute changes to the CDR region can impact binding affinities. (see Figure 2, effects of CDR mutations on binding affinity), respectively. Rudikoff et al (Single amino acid substitution altering antigen-binding specificity. Proc Natl Acad Sci U S A. 1982 Mar;79(6):1979-83) teaches that single amino acid substitutions alter antigen-binding specificity. [Abstract] L stly, Herold et al (Sci Rep. 2017 Sep 25;7(1):12276) teaches and demonstrates that single and double mutations in exemplary antibodies, and found that single point mutations in the VH CDR region can completely abolish antigen binding. [see pg 8]
To provide adequate written description and evidence of possession of the claimed antibody genus, the instant specification can structurally describe representative NEO-201 antibodies that function as claimed, or describe structural features common to the members of the genus which features constitute a substantial portion of the genus. Alternatively, the specification can show that the claimed invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics (see University of California v. Eli Lilly and Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997) and Enzo Biochem, Inc. V. Gen-Probe Inc.). A disclosure that does not adequately describe a product itself logically cannot adequately describe a method of using that product.
Although Applicants may argue that it is possible to screen for NEO-201 antibodies and function as claimed, the court found in (Rochester v. Searle, 358 F.3d 916, Fed Cir., 2004) that screening assays are not sufficient to provide adequate written description for an invention because they are merely a wish or plan for obtaining the claimed chemical invention. “As we held in Lilly, “[a]n adequate written description of a DNA … ‘requires a precise definition, such as by structure, formula, chemical name, or physical properties,’ not a mere wish or plan for obtaining the claimed chemical invention.” 119 F.3d at 1566 (quoting Fiers, 984 F.2d at 1171). For reasons stated above, that requirement applies just as well to non-DNA (or RNA) chemical inventions.” Knowledge of screening methods provides no information about the structure of any future binding proteins or antibodies yet to be discovered that may function as claimed. The NEO-201 antigen provides no information about the structure of an antibody that binds to it and treats cancer.
In this case, the only factor present in the claims is a recitation of the antibody function. The instant specification fails to describe structural features common to the members of the genus, which features constitute a substantial portion of the genus because the instant specification discloses only a single exemplary antibody that functions as claimed. A definition by function does not suffice to define the genus because it is only an indication of what the antibody does, rather than what it is. Other than the one antibody, the specification fails to provide any structural features coupled to the claimed functional characteristics.
Applicants have not established any reasonable structure-function correlation with regards to the sequences of the claimed antibody that can be altered and still maintain function. Therefore, one could not readily envision members of the broadly claimed genus.
Given the lack of representative examples to support the full scope of the claimed antibody required to practice the claimed methods, the present claims lack adequate written description. The specification discloses only one example of an NEO-201 antibody, does not disclose any multispecific or bispecific antibodies, nor any CAR-T cells comprising the instantly claimed antibodies, or does not disclose any representative variants of the antibody with less than 100% SEQ ID Nos. Thus, the specification does not provide an adequate written description of the antibody that is required to practice the claimed invention. Since the specification fails to adequately describe the product to which the claimed method uses, it also fails to adequately describe the method.
Regarding cancer vaccine:
The written description is on treatment of the cancer vaccine as recited by the claim above. It has been interpreted that one of skill in the art cannot construct a cancer vaccine without knowing what the structure or the target of the vaccine. It is not clear how one can make and administer a cancer vaccine without knowing the structure of the vaccine. The claims recite that the method includes “treating” the subject, the instant specification defines “treating” or “treatment” in paragraph 0180 of the published specification. Thus, it has been interpreted that the cancer vaccine must be capable of inducing an immune response in a patient, as well as treatment function. The definition of a vaccine in the online Merriam-Webster on-line dictionary is a preparation that is administered (as by injection) to stimulate the body’s immune response against a specific infectious agent or disease.
The instant specification does not disclose any examples of an anti-cancer vaccine. The instant specification does not provide adequate written description of the claimed genus of “cancer vaccines.”
The MPEP further states that if a biomolecule is described only by a functional characteristic, without any disclosed correlation between function and structure of the sequence, it is “not sufficient characteristic for written description purposes, even when accompanied by a method of obtaining the claimed sequence.” MPEP 2163. The MPEP does state that for generic claim the genus can be adequately described if the disclosure presents a sufficient number of representative species that encompass the genus. MPEP 2163. If the genus has a substantial variance, the disclosure must describe a sufficient variety of species to reflect the variation within that genus. See MPEP 2163. Although the MPEP does not define what constitute a sufficient number of representative, the Courts have indicated what do not constitute a representative number species to adequately describe a broad generic. In Gosteli, the Court determined that the disclosure of two chemical compounds within a subgenus did not describe that subgenus. In re Gosteli, 872 F.2d at 1012, 10 USPQ2d at 1618.
The specification does not provide adequate written description of the claimed invention. The legal standard for sufficiency of a patent's (or a specification's) written description is whether that description "reasonably conveys to the artisan that the inventor had possession at that time of the. . .claimed subject matter", Vas-Cath, Inc. V. Mahurkar, 19 USPQ2d 1111 (Fed. Cir. 1991). In the instant case, the specification does not convey to the artisan that the Applicant had possession at the time of invention of the claimed invention, the cancer vaccine.
The Federal Circuit addressed the application of the written description requirement to DNA-related inventions in University of California v. Eli Lilly and Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997). The court stated that “[a] written description of an invention involving a chemical genus, like a description of a chemical species, requires a precise definition, such as by structure, formula, [or] chemical name, of the claimed subject matter sufficient to distinguish it from other materials.” Id. At 1567, 43 USPQ2d at 1405. The court concluded that “naming a type of material generally known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material.” Id.
In this case, the specification does not describe the genus of that are capable of functioning in a vaccine that satisfies either the Lilly or Enzo standards. The instant specification does not disclose any examples of an anti-cancer vaccine. The instant claims attempt to claim every type of cancer vaccine and do not limit it to any specific type of cancer vaccine. A search of the art demonstrates the complexity and challenges of utilizing cancer vaccines. Gracia-Grijo et al. (Frontiers in Immunology 2019 10 1-19) teaches the complications of cancer vaccines targeting neoantigens. Gracia-Grijo teaches although clinical trials testing vaccines targeting neoantigens have demonstrated they are safe and well tolerated, whether individualized immunotherapies targeting neoantigens can mediate effective antitumor responses in a broader patient population, remains an open question. Gracia-Grijo teaches that despite all the technological innovation and development of novel screening assays, the rapid and precise identification of the bona fide neoantigens in any given patient remains a major hurdle that will need to be overcome to translate the potential of neoantigen targeting into effective therapies for patients with cancer. [Conclusion, pg 14] Hu et al (Nature Reviews Immunology 2018 18, 168–182) teaches the complications of cancer vaccine production and use, including but not limited to, tumor heterogeneity between and within tumors is a major challenge to the development of cancer immunology. [pg 3, building cancer vaccines] The specification does not disclose sufficient examples of cancer vaccines that are capable of treating cancer.
Thus, the specification does not provide an adequate written description of the genus of cancer vaccines that is required to practice the claimed invention. The instant disclosure does not adequately describe the scope of the claimed genus, which encompasses a substantial variety of subgenera. Since the disclosure fails to provide sufficient relevant identifying characteristics, and because the genus is highly variant, one of skill in the art would reasonably conclude that the disclosure fails to provide a representative number of species to describe the genus as broadly claimed.
Claims 1, 4, 14-16, 22, 23, and 29-30 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 treating a hematological malignancy, does not reasonably provide enablement for preventing a hematological malignancy. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
BREADTH OF THE CLAIMS: The claims are drawn to a method of treating or preventing a hematological malignancy and/or decreasing the burden of a hematological malignancy, or slowing the growth or proliferation rate of a hematological malignancy and/or killing malignant hematological cells in a patient in need thereof, comprising administering to the patient an effective amount of an antibody or antibody fragment which binds to glycosylated CEACAM5 and CEACAM6 but not to aglycosylated CEACAM5 or aglycosylated CEACAM6, optionally wherein the antibody is NEO- 201 or an antibody comprising the same CDRs as NEO-201.
PRESENCE OR ABSENCE OF EXAMPLES: The instant specification does not disclose any examples that the claimed antibody prevent a hematological malignancy.
STATE OF THE ART: A search of relevant art, does not reveal any demonstration that the combination of an sulfonamide inhibitor and an immune checkpoint inhibitor prevents cancer. Cancer has a wide variety of causes, from environmental and/or developmental exposure to ionizing radiation and/or chemical exposure in addition to some types viral and bacterial exposure (Lichtman MA et al. The Oncologist 2017; 22(5); 542–548). Even though cancer is featured by the infinite cell proliferation, its pathogenesis is extremely complex and related to many mechanisms. In general, the hallmarks of cancer consist of ten biological capabilities during the development of cancers, namely sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, activating invasion and metastasis, tumor-promoting inflammation, genome instability and mutation, evading immune destruction and reprogramming energy metabolism (Hanahan D et al. Cell 2011 144(5) p646-674, Figures 1 and 3). More than 100 types of cancer have been identified which are typically termed for the organs or tissues where they occur. Hanahan taught over the past decade, tumors have increasingly been recognized as organs whose complexity approaches and may even exceed that of normal healthy tissues (page 661, right column second to last paragraph). Hanahan taught many human tumors are histopathologically diverse, containing regions demarcated by various degrees of differentiation, proliferation, vascularity, inflammation, and/or invasiveness (page 662, left column, first paragraph). Szabo et al (Selecting targets for cancer prevention: where do we go from here? Nat Rev Cancer 6, 867–874; 2006) teaches the intricacies and complications of cancer prevention. Szabo teaches that in addition to efficacy and toxicity concerns of cancer drugs targeting functions, there are a number of practical issues that should be considered, including drug formulation and dosing schedule to ensure adherence, as well as the cost. Szabo also teaches that in some cases the targets selected for drug therapy may even cause harm. [Whole document]
Clinical trials aimed at proving preventative cancer activity attributable to a specific intervention are largely infeasible, due to the impossibly large number of subjects and an equally impossible long timeframe. Although cancer is a common disease, specific types of cancer are still relatively infrequent events in an otherwise healthy population. Therefore, trials with cancer incidence as endpoints would necessarily involve several thousands of subjects followed for several decades. Such logistic difficulties have precluded cancer prevention trials with cancer incidence as an endpoint in all but a selected few malignancies for treatments such as tamoxifen and finasteride (Lee KW et al. Nature Reviews Cancer 2011 11 211-218, page 211, left column last paragraph) The prior art does not demonstrate that the NEO-201 antibody does not prevent recurrence of carcinoma, rather it shows that NEO-201 is a novel antibody and further studies need to be conducted for further therapeutic efficacies.
PREDICTABILITY: The specification lacks the critical steps necessary in presenting some type of predictable response in a population of hosts deemed necessary to prevent hematological malignancy comprising administering an antibody that binds to glycosylated CEACAM5 AND 6, such as NEO-201. There is no evidence in the instant application or the art that as noted in the prior that demonstrate that an antibody that treats cancer would prevent the onset of cancer in subjects as claimed. The amount of experimentation required to formulate such guidance would be enormous; one would have to demonstrate the efficacy of the combination in several models across several different types of cancers and determine the appropriate regimen (doses and frequency) for use of the combination or composition in a preventative setting. Further, one would have to conduct population analysis to identify definitive characteristics which indicate that a subject is at risk of developing any cancer to a degree that would outweigh potential adverse effects of treatment with the claimed combination or composition. Thus, considering the high level of skill in the art, the state of the art, the level of predictability, and the guidance and examples provided, the experimentation required to enable the full scope of the claimed invention would not be reasonable.
QUANTITY OF EXPERIMENTATION: Undue experimentation would be required to determine if the claimed antibody could predictably prevent cancer as claimed. MPEP 2164.01 recites that “The test of enablement is not whether any experimentation is necessary, but whether, if experimentation is necessary, it is undue. In re Angstadt, 537 F.2d 498, 504, 190 USPQ 214, 219 (CCPA 1976)”. The experimentation needed to practice this method is undue and unreasonable as it requires determining whether the claimed antibody prevents cancer. A person skilled in the art will not be able to use the invention without undue experimentation. (In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988))
Accordingly, the instant claims do not comply with the enablement requirement of §112, since to practice the invention claimed in the patent a person of ordinary skill in the art would have to engage in undue experimentation, with no assurance of success.
Claims 29 and 30 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 treating a hematological malignancy comprising administering the antibody alone, does not reasonably provide enablement for further administering another therapeutic agent to said patient. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
BREADTH OF THE CLAIMS: Claim 29 is drawn to a method further comprising administering another therapeutic agent to said patient. Claim 30 lists examples of agents that can be combined with the claimed antibody.
PRESENCE OR ABSENCE OF EXAMPLES: The instant specification does not disclose any examples that the claimed antibody prevents a hematological malignancy.
STATE OF THE ART: It is well known that the art of anti-cancer therapy is highly unpredictable, for example, Gura (Science, 1997, 278:1041-1042) teaches that researchers face the problem of sifting through potential anticancer agents to find ones promising enough to make human clinical trials worthwhile and teach that since formal screening began in 1955, many thousands of drugs have shown activity in either cell or animal models that only 29 have actually been shown to be useful for chemotherapy See p. 1041, see 1st and 2nd para. Furthermore, Kaiser (Science, 2006, 313: 1370) teaches that 90% of tumor drugs fail in patients. See 3rd col., 2nd to last para. Additionally, Chames et al (British J. of Pharmacology, 2009, 157, 220-233) teach that there are several challenges to development therapeutic antibodies. These challenges include functional limitations such as inadequate pharmacokinetics, tissue accessibility and impaired interactions with the immune system (Abstract). Additionally, Chames teaches several limitations of therapeutic antibodies such as affinity between the antibody and its antigen, competition with patient’s IgG, and efficiency issues in triggering the immune response (pages 224-225). Fantini et al teaches that NEO-201 is a novel humanized IgG1 monoclonal antibody and found to be reactive against human carcinoma cell lines and that this art teaches that this is a novel agent that warrants clinical testing as a therapeutic agent. Further demonstrating that the combination with other agents as not been demonstrated.
PREDICTABILITY: The specification lacks the critical steps necessary in presenting some type of response in a population of hosts deemed necessary to treat hematological malignancies comprising administering the claimed antibody with any of the agents listed in claim 30. The amount of experimentation required to formulate such guidance would be enormous; one would have to demonstrate the efficacy of the combination in several models across and determine the appropriate regimen (doses and frequency) for use of the combination or composition in a treatment setting. Thus, considering the high level of skill in the art, the state of the art, the level of predictability, and the guidance and examples provided, the experimentation required to enable the full scope of the claimed invention would not be reasonable.
QUANTITY OF EXPERIMENTATION: Undue experimentation would be required to determine if the claimed antibody and what agent could treat cancer as claimed. MPEP 2164.01 recites that “The test of enablement is not whether any experimentation is necessary, but whether, if experimentation is necessary, it is undue. In re Angstadt, 537 F.2d 498, 504, 190 USPQ 214, 219 (CCPA 1976)”. The experimentation needed to practice this method is undue and unreasonable as it requires determining whether which agent and claimed antibody treats cancer. A person skilled in the art will not be able to use the invention without undue experimentation. (In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988))
Accordingly, the instant claims do not comply with the enablement requirement of §112, since to practice the invention claimed in the patent a person of ordinary skill in the art would have to engage in undue experimentation, with no assurance of success.
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 30 and 36 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.
Regarding claims 30 and 36 the phrase "such as" 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 30 contains the trademark/trade name KEYTRUDA®, OPDIVO ®, LIBTAYO ®, TECENTRIQ ®, IMFINZI ®, and BAVENCIO ®. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe antibodies and, accordingly, the identification/description is indefinite.
Claim Rejections - 35 USC § 102
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, 14, 15, 36, 39, and 42 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Arlen et al (WO2019160970 A1; published 8/22/2019).
It is noted that the instant specification discloses the following:
16c3 is an example of the NEO-201 encompassed by claim 1. The sequences of 16c3 (SEQ ID Nos: 28 and 29) is disclosed on page 50 of the instant specification.
Arlen teaches a method of treating a hematological malignancy comprising administering an effective amount of an antibody that binds to CEACAM5 or CEAAM6, wherein the antibody is NEO-201, such as antibody 16c3. [13, 44, 45, 55, 121]. Arlen teaches that NEO-201 binds to cancer-associated variants of CEACAM5 and CEACAM6, specifically via a cancer-associated glycosylation variant of these proteins. [12-13] Regarding claim 14, Arlen teaches determining that the hematological malignancy is CEACAM5 and/or CEACAM6 positive. [27-28] Regarding claims 15 and 32, Arlen teaches that the antibody may be humanized, conjugated to another moiety, such as cytotoxic moiety, radioactive moiety or affinity tag, and that NEO-201 is capable of mediating both ADCC and CDC against tumor cells. [50-54] Regarding claims 29 and 30, Arlen teaches that the antibody may be combined with another therapeutic agent, such as an immune checkpoint inhibitor, PD-1 or CTLA-4 inhibition. [7, 30] Regarding claim 34, Arlen further teaches that NEO-201 has been demonstrated to attenuate human tumor xenografts in mice and demonstrates safety and tolerability. [8, 12-13] Regarding claims 36 and 39, Arlen teaches a method of detecting the expression of the NEO-201 antigen by hematological malignancy cells by staining hematological cells in a patient sample by contacting the cells with a NEO-201 antibody. [27-28] Arlen teaches that the sample comprises a blood sample. [70-72]
With regards to the antibody binding to glycosylated CEACAM5 and CEACAM6 but not to glycosylated CEACAM5 or CEAAM6, the Applicant exemplifies an example of this antibody as NEO-201, it is noted that while new and non-obvious uses of old compositions may be patentable, MPEP § 2112.02(II) states that “when the claim recites using an old composition or structure and the ‘use’ is directed to a result or property of that composition or structure, then the claim is anticipated. In re May, 574 F.2d 1082, 1090, 197 USPQ 601, 607 (CCPA 1978)”. Products of identical composition cannot have mutually exclusive properties. See MPEP § 2112.01.
Claim(s) 1, 4, 14-16, 22, 23, 29-30, 32, 34-36, 39 and 42 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Jones et al (WO2018218230 A1; Published 11/29/2018).
It is noted that the instant specification discloses the following:
16c3 is an example of the NEO-201 encompassed by claim 1. The sequences of 16c3 (SEQ ID Nos: 28 and 29) is disclosed on page 50 of the instant specification.
Jones teaches a method of treating a hematological malignancy comprising administering an anti-CEA antibody, NEO-201. [0165] Regarding claims 4, 22 and 23, Jones teaches that the hematological malignancy is leukemia, acute myeloid leukemia, or multiple myeloma, or overexpress CEACAM5 or CEACAM6. [0182-0183] [0165] Regarding claim 14, Jones teaches that CEA are expressed in different cell types and are involved in various biological process, including angiogenesis. Jones teaches that these levels are overexpressed with CEACAM6 and CEACAM6. Regarding claim 15, Jones teaches that the NEO-201 antibody is humanized. [0256, 0259] Regarding claims 19 and 47, Jones teaches that the NEO-201 antibody is a monoclonal antibody “16C3”. [see at least 0253-0258] Regarding claim 16, Jones teaches that the antibody is administered as an immune cell which expresses the antibody. [0249-0250] Regarding claim 29 and 30, Jones teaches a method of combining a therapeutic agent, such as an anti-CTLA-4 antibody or anti-PD-1 antibody with the antibody. [0265-0267] Regarding claim 32, Jones teaches that the hematological malignancy cells are killed by CDC. [0250] Regarding claim 35, Jones teaches further comprising contacting hematological malignancy cells with effector cells, such as killer cells. [0031, 0057, 0246-0247] ([0165, 0259, 0260, 0337, 0348]; Claims 70-71, 81, 82, 140-143, 154-156, 192, and 200-203).
With regards to the antibody binding to glycosylated CEACAM5 and CEACAM6 but not to glycosylated CEACAM5 or CEAAM6, the Applicant exemplifies an example of this antibody as NEO-201, it is noted that while new and non-obvious uses of old compositions may be patentable, MPEP § 2112.02(II) states that “when the claim recites using an old composition or structure and the ‘use’ is directed to a result or property of that composition or structure, then the claim is anticipated. In re May, 574 F.2d 1082, 1090, 197 USPQ 601, 607 (CCPA 1978)”. Products of identical composition cannot have mutually exclusive properties. See MPEP § 2112.01.
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.
Claim(s) 1, 4, 14-16, 22, 23, 29-30, 32, 34-36, and 39-42 are rejected under 35 U.S.C. 103 as being unpatentable over Jones et al (WO2018218230 A1; Published 11/29/2018), in view of Arlen et al (WO2019160970 A1; published 8/22/2019).
It is noted that the instant specification discloses the following:
16c3 is an example of the NEO-201 encompassed by claim 1. The sequences of 16c3 (SEQ ID Nos: 28 and 29) is disclosed on page 50 of the instant specification.
Jones teaches a method of treating a hematological malignancy comprising administering an anti-CEA antibody, NEO-201. [0165] Regarding claims 4, 22 and 23, Jones teaches that the hematological malignancy is leukemia, acute myeloid leukemia, or multiple myeloma, or overexpress CEACAM5 or CEACAM6. [0182-0183] [0165] Regarding claim 14, Jones teaches that CEA are expressed in different cell types and are involved in various biological process, including angiogenesis. Jones teaches that these levels are overexpressed with CEACAM6 and CEACAM6. Regarding claim 15, Jones teaches that the NEO-201 antibody is humanized. [0256, 0259] Regarding claims 19 and 47, Jones teaches that the NEO-201 antibody is a monoclonal antibody “16C3”. [see at least 0253-0258] Regarding claim 16, Jones teaches that the antibody is administered as an immune cell which expresses the antibody. [0249-0250Regarding claim 29 and 30, Jones teaches a method of combining a therapeutic agent, such as an anti-CTLA-4 antibody or anti-PD-1 antibody with the antibody. [0265-0267] Regarding claim 32, Jones teaches that the hematological malignancy cells are killed by CDC. [0250] Regarding claim 35, Jones teaches further comprising contacting hematological malignancy cells with effector cells, such as killer cells. [0031, 0057, 0246-0247] ([0165, 0259, 0260, 0337, 0348]; Claims 70-71, 81, 82, 140-143, 154-156, 192, and 200-203).
However, Jones does not explicitly teach the method of claims 40-41.
Arlen teaches that NEO-201 binds to cancer-associated variants of CEACAM5 and CEACAM6, specifically via a cancer-associated glycosylation variant of these proteins, and that NEO-201 is capable of mediating both ADCC and CDC against tumor cells. Arlen further teaches that NEO-201 has been demonstrated to attenuate human tumor xenografts in mice and demonstrates safety and tolerability. [8, 12-13] Arlen teaches the use of NEO-201 antibody for the treatment of hematologic malignancies. [44, 45, 55] Arlen teaches that the antibody may be humanized, conjugated to another moiety, such as cytotoxic moiety, radioactive moiety or affinity tag. [050-054] Arlen teaches that the antibody may be combined with another therapeutic agent, such as an immune checkpoint inhibitor, PD-1 or CTLA-4 inhibition. [7, 30] Arlen teaches a method of detecting the expression of the NEO-201 antigen by hematological malignancy cells by staining hematological cells in a patient sample by contacting the cells with a NEO-201 antibody. [27-28] Arlen teaches that the sample comprises a blood sample. [70-72] Arlen teaches separating NEO-201 positive cells from NEO-201 negative cells by fluorescence activated cell sorting. Arlen teaches that the cells are isolated by contacting sample with a support comprising a NEO-201 antibody. [36-40]
It is noted that claim(s) 40-41 require separating NEO-201 positive hematological malignancy cells from NEO-201 negative cells. This limitation would have been obvious to those of ordinary skill in the art because: (1) Jones teaches the method of detecting CEACAM5 AND CEACAM6 (NEO-201 antigens), (2) Arlen teaches a method of detecting the expression of the NEO-201 antigen by hematological malignancy cells by staining hematological cells in a patient sample by contacting the cells with a NEO-201 antibody, 16c3, (3) Arlen teaches known methods of separating NEO-201 positive malignancy cells from NEO-201 negative cells by fluorescence activated cell sorting and (4) Arlen teaches that the cells are isolated by contacting sample with a support comprising a NEO-201 antibody. Although, Arlen teaches the methods in separating T-reg cells, one of skilled in the art could have applied this known method to separate NEO-201 positive cells in hematological malignancies, with a reasonable expectation of success.
Conclusion
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/SARAH A ALSOMAIRY/Examiner, Art Unit 1646
/Zachariah Lucas/Supervisory Patent Examiner, Art Unit 1600
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