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 1-12 and 15-22 are pending.
Claim Objections
Claim 7 is objected to because of the following informalities: Claim 7 recites the word “ypically”. This appears to be typically misspelled. Appropriate correction is required.
Claim objected to because of the following informalities: Claim 8 has an extra space between “intracellular domain, and the CD28 intracellular domain. Appropriate correction is required.
Claim objected to because of the following informalities: Claim 10 recites “(currently amended0. 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 1-12 and 15-22 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.
PARTIAL STRUCTURE:
The claims are drawn to a humanized synthetic single domain antibody (hsdAb) directed against HER2 (anti-HER2 sdAb), wherein said anti-HER2 sdAb has the following formula FR-1-CDR1-FR2-CDR2-FR3-CDR3-FR5, and wherein the CDRs are selected from (a)-(f), or g, which recites CDR1, CDR2, and CD4 as defined in any of a-f further having one or more conservative amino acid modifications in one or more these CDRs.
Dependent claim 2 and 6 recites that the anti-HER2 sdAb according to claim 1 comprising: a sequence having at least 90% identity with a sequence from the group consisting of: SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, and SEQ ID NO: 28.
Thus, the claims recite only a partial structure of the anti-HER2 sdAb, wherein there could be unlimited conservative amino acid modifications, and at least 10% sequence discrepancy from the sequences recited in the dependent claims.
The instant specification does not disclose any representative variants of the hsdAb with less than 100% SEQ ID Nos: that function to bind to HER2.
It is well known in the art that that 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] Lastly, 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 antibodies comprising the instantly claimed sequences, the instant specification can structurally describe representative antibodies, 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.).
Applicants have not established any reasonable structure-function correlation with regards to the sequences of the anti-HER2 sdAb 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 antibodies, and lack of reasonable structure-function correlation with regards to the unknown variant sequences that can be altered and still maintain binding function, the present claims lack adequate written description. Thus, the specification does not provide an adequate written description of the vast genus of sequence variant antibodies, that is required to practice the claimed inventions.
SECOND ANTIGEN BINDING COMPOUND & ADDITIONAL THERAPEUTIC AGENT
Dependent claim 5 recites a multivalent binding compound comprising at least a first sdAb consisting in the anti-HER2 sdAb according to claim 1, and comprising at least a second antigen binding compound directed against an antigen selected from a polypeptide, a protein, or a small molecule.
Dependent claim 7 recites a multivalent compound or a CAR comprising at least a first sdAb consisting in the anti-HER2 sdAb according to claim 1, wherein a second antigen is selected from the group consisting of antigens other than HER2 can be selected from SMA, PSCA, BCMA, CS1, GPC3, CSPG4, EGFR, HER3, CA125, CD 123, 5T4, IL-13R, CD2, CD3, CD16 (FcγRIII), CD19, CD20, CD22, CD33, CD23, L1 CAM, MUC16, ROR1, SLAMF7, cKit, CD38, CD53, CD71, CD74, CD92, CD100, CD123, CD138, CD146 (MUC18), CD148, CD150, CD200, CD261, CD262, CD362, ROR1, mesothelin, CD33/IL3Ra, c-Met, Glycolipid F77, EGFRvlll, MART-1, gp100, GD-2, 0-GD2, NKp46 receptor, presented antigens like NY-ESO-1 or MAGE A3, human telomerase reverse transcriptase (hTERT), survivin, cytochrome P450 1 B1 (CY1 B), Wilm's tumor gene 1 (WT1), livin, alphafetoprotein (AFP), carcinoembryonic antigen (CEA), mucin 16, MUC1, p53, cyclin, and an immune checkpoint target or combinations thereof.
Dependent claim 22 recites a method of the treatment of cancer in a subject in need thereof comprising administering a therapeutically efficient amount of the humanized anti-HER2 sDAb according to claim 1, wherein said humanized anti-HER2 sdAb is used in combination with at least one further therapeutic agent, wherein said at least one further therapeutic agent is an anticancer agent.
The instant specification does not disclose (1) the structure of the second antigen binding compound. Regarding the therapeutic agent, the instant specification discloses that the anti-cancer agent may be a chemotherapeutic agent, an immunotherapeutic agent, and optionally a checkpoint inhibitor. The instant specification does not disclose any examples of the second antigen binding compound or the additional therapeutic agent.
With regards to any therapeutic agent that combined with the anti-HER2 agent, the art discloses the complications and challenges of any therapeutic agent used to treat cancer. Anand et al (Cancer chemotherapy and beyond: Current status, drug candidates, associated risks and progress in targeted therapeutics. Genes Dis. 2022;10(4):1367-1401. Published 2022 Mar 18) teaches different approaches of therapies for anticancer treatment, but also teaches the challenges associated with these therapies. Anand teaches that the selection of chemo drugs or the combination drugs is challenging because of the relapse of the disease due to drug resistance. [pg 1369, 1st column] Anand also teaches that genetic diversity also poses additional challenges to targets all kinds of cells in a particular tissue owing to the tumor heterogeneity. [pg 1372, 1st column] Lopez et al (Combine and conquer: challenges for targeted therapy combinations in early phase trials. Nat Rev Clin Oncol. 2017;14(1):57-66) teaches that the challenges include finding the best combination to explore and that the scale of biological complexity of the mechanisms of resistance to targeted treatment is large and requires several novel approaches. Thus, without knowing the exact structure, pharmacokinetic, or pharmacodynamic effects of the therapeutic agent combined with claimed antibody, the claimed method fails to provide adequate support for the therapeutic agent as claimed.
Regarding the second antigen binding compound: 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). The structure activity relationship of the CDR antigen binding region that binds to the specific targets as claimed are not known and the binding epitopes cannot be predicted based on the antibody sequences.
To provide adequate written description and evidence of possession of the claimed composition therapeutic agent genus, the instant specification can structurally describe representative agents, including antibodies, 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 agents, or antibodies, that 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 agent yet to be discovered that may function as claimed. EGFR, VEGF, VEGFR2, CTLA4, PD-L1, HER2, CD20, Trop2, Lag3, TIGIT, CD27, OX40, ICOS, BTLA, TIM3, BCMA, c-MET, and TAA-1/2/3.antigens provides no information about the structure of the agent that inhibits them.
Given the lack of representative examples to support the full scope of the claimed therapeutic agent that inhibit one or more activities of any of the claimed targets, and lack of reasonable structure-function correlation with regards to the unknown sequences in the variable domains or CDRs of the antibodies that function as claimed, the present claims lack adequate written description. Thus, the specification does not provide an adequate written description of antibodies 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.
Claims 5, 7, 16, 17, and 22 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 use of the anti-HER2 sdAb as monotherapy, does not reasonably provide enablement for in combination with other agents. 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 the combination of the anti-HER2 sdAb with another agent (a second antigen binding compound or another therapeutic agent). There is no support for the instantly claimed combinations:
Dependent claim 5 recites a multivalent binding compound comprising at least a first sdAb consisting in the anti-HER2 sdAb according to claim 1, and comprising at least a second antigen binding compound directed against an antigen selected from a polypeptide, a protein, or a small molecule.
Dependent claim 7 recites a multivalent compound or a CAR comprising at least a first sdAb consisting in the anti-HER2 sdAb according to claim 1, wherein a second antigen is selected from the group consisting of antigens other than HER2 can be selected from SMA, PSCA, BCMA, CS1, GPC3, CSPG4, EGFR, HER3, CA125, CD 123, 5T4, IL-13R, CD2, CD3, CD16 (FcγRIII), CD19, CD20, CD22, CD33, CD23, L1 CAM, MUC16, ROR1, SLAMF7, cKit, CD38, CD53, CD71, CD74, CD92, CD100, CD123, CD138, CD146 (MUC18), CD148, CD150, CD200, CD261, CD262, CD362, ROR1, mesothelin, CD33/IL3Ra, c-Met, Glycolipid F77, EGFRvlll, MART-1, gp100, GD-2, 0-GD2, NKp46 receptor, presented antigens like NY-ESO-1 or MAGE A3, human telomerase reverse transcriptase (hTERT), survivin, cytochrome P450 1 B1 (CY1 B), Wilm's tumor gene 1 (WT1), livin, alphafetoprotein (AFP), carcinoembryonic antigen (CEA), mucin 16, MUC1, p53, cyclin, and an immune checkpoint target or combinations thereof.
Dependent claim 22 recites a method of the treatment of cancer in a subject in need thereof comprising administering a therapeutically efficient amount of the humanized anti-HER2 sDAb according to claim 1, wherein said humanized anti-HER2 sdAb is used in combination with at least one further therapeutic agent, wherein said at least one further therapeutic agent is an anticancer agent.
STATE OF THE ART: It is well known that the art of anti-cancer therapy is highly unpredictable. Lopez et al (Combine and conquer: challenges for targeted therapy combinations in early phase trials. Nat Rev Clin Oncol. 2017;14(1):57-66) teaches that the challenges include finding the best combination to explore and that the scale of biological complexity of the mechanisms of resistance to targeted treatment is large and requires several novel approaches. Lopez also teaches that there are hundreds of targeted treatments and the number of combinations trials outweigh the number of patients who can be entered into trials to evaluate them. Lopez also teaches that combination therapy in clinic results into issues including toxicity, pharmacokinetic interactions and finding the correct timing and context of using these combinations [pg 3, 2nd paragraph] Furthermore, 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. 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). Thus, it is unpredictable to claim that an anti-HER2 can be combined with any therapeutic agent, including other therapeutic antibodies.
PRESENCE OR ABSENCE OF EXAMPLES: The instant specification does not disclose any examples of any therapeutic agent, a second antigen binding compound, in combination with the claimed anti-HER2 sdAb.
PREDICTABILITY: Reasonable correlation must exist between the scope of the claims and scope of enablement set forth, and it cannot be reasonably predicted that administration of an anti-HER2 antibody can be combined with any other therapeutic agent and treat cancer or tumors.
QUANTITY OF EXPERIMENTATION: Undue experimentation would be required to determine which therapeutic agent is administered with the claimed anti-HER2 sdAb to treat cancer and, 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 exactly which agent can be combined with the claimed anti-HER2 antibody, and is not routine in the art as these diseases are unrelated and comprise various subgroups within each disease state. 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.
Closest Prior Art
The closest prior art made of record is Chen et al (WO2019135159 A2; Published 7/11/2019; cited in IDS 6/26/2023). Chen teaches the use of single-domain antibodies targeting HER2. (whole document) However, Chen does not recite the specific sequences of the claimed single domain antibody targeting HER2.
Conclusion
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/SARAH A ALSOMAIRY/Examiner, Art Unit 1646
/Zachariah Lucas/Supervisory Patent Examiner, Art Unit 1600