DETAILED ACTION
Applicant’s claim amendments and arguments in the response filed 6/8/2026 are acknowledged and entered into the record.
Accordingly, Claims 1-7, 9-12, 14-21 are pending and will be examined on the merits.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Objections
Claim 14 is objected to because of the following informalities: Claim 14 depends from cancelled Claim 13. Appropriate correction is required. For examination purposes Claim 14 will be examined as depending from Claim 12.
Claim Rejections Maintained - 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 1-7, 9-12, 14-21 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 directed to methods of treating an anaplastic large cell lymphoma comprising administering a CAR-T cells engineered to express an antibody having binding affinity for ROR2 capable of inducing cell death of ROR2 expressing cancer cells. The claims recite an antibody function, capable of inducing cell death, without a correlating structure-to-function.
To provide adequate written description and evidence of possession of the claimed genus of agents and inhibitors the instant specification can structurally describe representative constructs 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.).
Although Applicants may argue that it is possible to screen for agents, 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.” The instant claims are drawn to a broad scope of ROR2 binding antibodies in a CAR-T cell format capable of inducing cell death of ROR2 expressing cancer cells, that would need to be tested in order to not only determine binding to at least one extracellular domain of ROR2 which leads to the depletion of ROR2, but their ability to induce cell death.
In this case, the only factor present in the claims is a recitation of “capable of inducing cell death of ROR2 expressing cancer cells” or “an antibody having binding affinity” for ROR2 without defining any structure to function correlation. 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 only discloses ROR2 expression in patient cells and does not provide any examples of the methods of treatment using the recited antibodies or CAR cells. A definition by function does not suffice to define the genus because it is only an indication of what the agent or inhibitor does, rather than what it is. The specification fails to provide any structural features coupled to the claimed functional characteristics. The instant specification fails to describe a representative number of sequences for the genus of antibodies that function as claimed. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus. Additionally, the structure of an antigen or epitope in no way predicts the inhibitors structure and sequence that will bind to it. Knowing the sequence structure of a protein in no way predicts or defines inhibitors which would bind and inhibit expression.
Applicants are directed to the recent and relevant decision in AbbVie Deutschland GmbH v. Janssen Biotech, Inc. (Fed. Cir. 2014). The court found that if the disclosed species only abide in a corner of the genus, one has not described the genus sufficiently to show that the inventor invented, or had possession of, the genus.
In the instant case, Applicants have not established any reasonable structure-function correlation with regards to what structure is capable of inducing cell death of ROR2 expressing cancer cells, or the antibody or chimeric antigen receptor structure/sequence required to bind to at least one extracellular domain of ROR2 which leads to the depletion of ROR2. Therefore one could not readily envision members of the broadly claimed genus. Because the genus of constructs encompassed by the claims is extensive and the artisan cannot envision the detailed structure of the encompassed constructs and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Thus one of skill in the art cannot "visualize or recognize" most members of the genus to show applicants were in possession of the invention at the time of filing.
Given the lack of representative examples to support the full scope of the claimed agents in the claimed method of treatment, and lack of reasonable structure-function correlation with regards to the unknown structure, the present claims lack adequate written description.
Response to Arguments
Applicant's arguments filed 6/8/2026 have been fully considered but they are not persuasive. Applicants argue case law that states “what is conventional or well known to one of ordinary skill in the art need not be disclosed in detail” and argue antibodies against ROR2 are not new and are conventional in the art and the instant claims are not directed to “inhibitors per se” but the method of using known inhibitors. Applicants point to their specification which discloses “various types of ROR2 antibodies suitable for use in the claimed methods.” These arguments have been carefully considered but not found persuasive.
The written description standard set out in Ariad applies to antibodies. See Amgen, Inc. v. Sanofl, 872 F.3d 1367, 1376-79 (Fed. Cir. 2017) (applying the Ariad standard to antibodies claimed based on their binding and blocking activities); AbbVie Deutschland GmbH & Co. v. Janssen Biotech, Inc., 759 F.3d 1285, 1298-1300 (Fed. Cir. 2014) (same). The claims here are directed to methods of using antibodies, rather than the antibodies themselves, but the same standard applies with regard to the written description requirement. See University of Rochester v. G.D. Searle & Co., 358 F.3d 916, 926 (Fed. Cir. 2004): Regardless whether a compound is claimed per se or a method is claimed that entails the use of the compound, the inventor cannot lay claim to that subject matter unless he can provide a description of the compound sufficient to distinguish infringing compounds from non-infringing compounds, or infringing methods from non-infringing methods. In University of Rochester, the “claimed method depended upon finding a compound that selectively inhibits PGHS-2 activity. Without such a compound, it is impossible to practice the claimed method of treatment.” Similarly here, the claimed methods cannot be practiced without antibodies having the binding activities recited in the claims. Applicant’s argument that the claims are adequately described because they are directed to a method, not a composition of matter, is therefore unpersuasive.
Secondly, Applicants are requiring ROR2 binding antibodies capable of inducing cell death, binding to an extracellular domain, capable of depleting ROR2 expressing cancer cells or preventing chemotherapy resistance. One of ordinary skill in the art, based on the disclosure, would not know what structure or CDR sequence is required for these functions, nor distinguish them from any other anti-ROR2 antibody previously known in the prior art. Although interactions of antibody binding domains with antigens have been described in the art, there is no teaching on how to predict the structures of antibodies that bind to an antigen based on a disclosure of an antigen. Padlan (Advances in Protein Chemistry, 1996, 49:57-133) reviewed the x-ray crystallographic data available for not only the structure of an antibody, but its interaction with an antigen. Padlan describes the contact residues on the antigen (the "epitope") and the contact residues on the antibody (the "paratope") for several antigen:antibody pairs in Section V, which begins on page 87. Of note, and as summarized in Table VII on page 92, the epitope on the antigen is only a limited number of residues, which may be either adjacent in the primary sequence or spatially distinct (discontinuous in the primary sequence, a “conformational” epitope). The general consensus is that a linear epitope is comprised of 9-22 continuous amino acids on a protein (page 606, left column, lines 3-8) and a conformational epitope is comprised of stretches of several linear epitopes where at least one of the linear epitope is at least 4-7 residues in length (Berglund et al, Protein Science, 2008, 17:606-613); specifically note on page 606, left column, lines 8-12 in particular). Therefore, the conformational epitope is a 3D structure that depends on the on the whole protein to be properly folded so that the required residues will be in the proper place to form the conformational epitope. While a crystal of an antibody bound to its antigen provides a detailed description of the residues that make up the epitope and the paratope, other techniques are used in the art to approximate the epitope. Corada (Blood, 2001; 97:1679-84) used recombinant fragments of the antigen and peptide scanning to map the general binding sites and specific residues on VE-cadherin that are recognized by a panel of antibodies (page 1682 “Identification of binding epitope of VE-cadherin mAbs”; figure 5). Corada et al. showed that the mAb “BV9” binds to an epitope that is located on both domains EC3-EC4 of VE-cadherin, suggesting a non-linear, conformational epitope (Figure 5). More in-depth peptide mapping analysis of mAb “BV6” identified a peptide sequence of six linear residues in the EC3 domain of VE-cadherin as the specific epitope (Table 1 and Figure 6). Computational analysis of proteins have been used to identify potential linear epitopes that would be specific for a particular protein (Berglund et al., abstract) and identify potential conformational epitopes on proteins (Kulkarni-Kale et al. Nucleic Acid Research, 2005, 33:W168-W171). Berglund et al. performed computational analysis of numerous protein sequences to identify unique residues on erbB-2 that can be used to generate specific antibodies for erbB-2 (Figure 4 in particular). Kulkarni-Kale et al. performed computational analysis of proteins with known structures to identify potential conformational epitopes on those proteins (abstract; page W168, see “Algorithm”). Thus, the 3D structure of proteins is required for identifying the potential conformational epitopes. However, the potential epitopes that are identified by these computational techniques will still need to be validated experimentally.
As shown by these prior art, the interaction of the antibody binding domain with an antigen and identifying potential epitopes on proteins have been well characterized. However, the prior arts do not teach how to predict the structural features of the antibodies that bind to a disclosed epitope. Thus, one still cannot predict the structural or functional features of plethora of antibodies that bind to a disclosed epitope. These and other studies on antibody epitopes do not provide sufficient information for a skill artisan to predict the structural and functional properties of a genus of antibodies that bind to a particular epitope based on the disclosure of an antibody epitope or species of antibodies that bind to a particular epitope.
Although anti-ROR2 antibodies are taught in the art, they are not sufficient for a skilled artisan to predict the structural features of the genus of anti-ROR2 specific antigen antibodies with the recited therapeutic benefits, and more particularly those used in a CAR format.
In this case, the variation encompassed by the present claims is large and the specification does not establish that the species described is representative of the claimed genus. Neither does the disclosure provide sufficient evidence that the structure provides a common structure sufficient to provide the claimed function of inducing cell death. The disclosure therefore does not show that Applicant is in possession of the necessary common attributes or features possessed by the members of the claimed genus. Accordingly, the skilled artisan would not recognize that Applicant is in possession of the invention as broadly claimed at the time the application was filed. Therefore, the rejection of record is hereby maintained.
New Grounds of Rejection
(based on re-consideration)
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, 2, 9, 12, 14-21 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. (PgPub 20210388086) and Nusse et al. (PgPub 20140322234).
The claims are drawn to a method of treating an anaplastic large cell lymphoma comprising administering a CAR-T cell expressing an antibody targeting ROR2 and capable of inducing cell death of ROR2 expressing cells. The claims are further drawn to method of preventing resistance to chemotherapy comprising administering a CAR-T cell expressing an antibody targeting ROR2 and capable of inducing cell death of ROR2 expressing cells.
Zhang et al. teach methods of treating cancer comprising administering a CAR-T cell, wherein the cell expresses anti-ROR2 (see paragraph [0101] and Claim 10). Zhang et al. disclose ROR2 levels of cancer cells in different blood cancer patients and lymphomas (see “embodiment 3” and Fig. 7 and 8). Zhang et al. disclose in “embodiment 4” a CAR-T expressing an anti-ROR2 antibody can kill target cells which express ROR2 and further disclose that further development of ROR2-CAR T cell therapy technology using high-affinity ROR2 antibodies should be developed for CAR-T cell therapy (see paragraph [0135]).
Nusse et al. teach ROR2 as a therapeutic target for cancers, including T-cell lymphomas (see paragraph [0098]. Nusse et al. disclose “antibodies that specifically bind to ROR2 are useful in decreasing or preventing the growth of tumor cells. Such antibodies may act in a variety of modalities, including: blocking the biological activity of ROR2, e.g. preventing ligand binding, altering ROR2 signaling pathways, etc., inducing cell death, e.g. by apoptosis, by antibody-dependent cell-mediated cytotoxicity (ADCC), by complement-dependent cytotoxicity (CDC)” (see paragraph [0009]).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use CAR-T cells expressing anti-ROR2 antibodies capable of inducing cell death for the treatment of anaplastic large cell lymphoma based on the teachings of Zhang et al. and Nusse et al. One of ordinary skill in the art would have been motivated to do so because Zhang et al. and Nusse et al. teach successful targeting of ROR2 expressing cells using an anti-ROR2-CAR-T cell to induce cell death and that several types of lymphomas express ROR2. Therefore, one of ordinary skill in the art would have had a reasonable expectation of success to treat patients suffering from anaplastic large cell lymphoma with anti-ROR2-CAR-T cells.
Conclusion
Claims 1-7, 9-12, 14-21 are rejected.
No claim is allowed.
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/Meera Natarajan/Primary Examiner, Art Unit 1643
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