DETAILED ACTION
Applicants claims filed 11/16/2023 are acknowledged and entered into the record. Accordingly, Claims 1-25 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 Rejections - 35 USC § 112
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.
Claim 9 recites the limitation "the TCR α" and “TCR β” in lines 1 and lines 2, respectively. There is insufficient antecedent basis for this limitation in the claim.
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, 3-8, 10-12, 19-21, 24 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 an antigen binding protein comprising 6 defined CDR sequences comprising SEQ ID NOs: 16, 32, 34, 10, 36, and 49, wherein one or more of the recited CDRs comprises at most one conservative amino acid substitution. The claim reads on variations within the CDR regions which can affect antigen binding. Furthermore, the claims do not recite a particular antigen for which the protein binds.
Thus, the instant specification describe novel engineered T cell receptors that specifically bind to the PRAME peptide. The specification discloses the sequence structure of said TCRs having specific substitutions within the CDR region. However, the broad scope of the instant claims read on an amino acid substitution within each of the 6 CDRs resulting in a factorial number of possible combinations. The specification does not provide sufficient representative examples or adequate description for the entire genus of PRAME binding TCR variants instantly claimed.
To provide adequate written description and evidence of possession of the antibody genus instantly claimed, the instant specification can structurally describe representative anti-PRAME TCRs that function to specifically bind the PRAME peptide 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 antibodies that bind the claimed epitope, 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.”
In this case, the only factor present in the claims is a recitation of having 6 CDR regions and a partial structure of sequence performing the claimed function: CDRs having at most one amino acid change compared to the respective reference sequences. 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 specific exemplary antibody sequence 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. The specification fails to provide a representative number of structural features coupled to the claimed functional characteristics because the specification discloses specific amino acid substitutions within the CDR regions that performs the function of binding PRAME. Therefore, the instant specification fails to describe a representative number of antibody sequences for the vast genus of PRAME binding TCRs 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.
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. He only described a portion of it. In Abbvie, the court stated: “It is undisputed that the structure of the antibody determines its antigen binding characteristic. In order to demonstrate that it has invented what is claimed, AbbVie's patents must adequately describe representative antibodies to reflect the structural diversity of the claimed genus. See Eli Lilly, 119 F.3d at 1568 (“[N]aming 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.”); Fiers v. Revel, 984 F.2d 1164. 1171 [25 USPQ2d 16011 (Fed. Cir. 1993) (“Claiming all DNA[s] that achieve a result without defining what means will do so is not in compliance with the description requirement; it is an attempt to preempt the future before it has arrived.”). Functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support, especially in technology fields that are highly unpredictable, where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus." In the instant case, Applicants have not adequately described representative antibodies to reflect the structural diversity of the claimed genus.
Furthermore, the art has established that structurally unrelated monoclonal antibodies can bind to the same epitope, therefore the PRAME protein sequence or epitope in no way predicts or provides information about an antibody’s sequence structure (i.e., the paratope), and the production, isolation, and characterization of a single monoclonal antibody specific for an epitope in no way provides any information about any other structurally distinct antibodies yet to be produced in the future that will bind to any epitopes comprised in the PRAME protein. Frank Immunology and Evolution of Infectious Disease, Chapter 4 “Specificity and Cross-Reactivity,” Princeton University Press, 2002, teaches: “Fourth, a particular epitope can be recognized by two different paratopes with no sequence similarity” (p. 37, cited on IDS filed 11/16/2023). Frank summarizes a study where it was found “two antibodies contact the same 12 amino acids of the antigen. However, the antibodies have different paratopes with no identical amino acids in the region that binds the antigen. The two antibodies also have different patterns of cross-reactivity with other antigens” (p. 37-38). van Regenmortel (Journal of Immunological Methods, 1998, 216:37-48, cited on IDS filed 11/16/2023) teaches: “As illustrated in Fig. 2, the orientation of the CDR loops with respect to the antigenic site may be different for each paratope. This figure also illustrates an interesting feature of epitope-paratope interactions, namely that the same antigenic site can be recognized by two paratopes showing no sequence similarity whatsoever” (p. 44, col. 2; Figure 2).
As was well-known in the antibody art, antibodies as a class share an overall structure generally comprising two heavy chain polypeptides that each comprises a heavy chain variable region (VH) and a heavy chain constant region made up of several domain (CH1, hinge, CH2, CH3, and for some antibodies, a CH4). Each of the heavy chains pairs with a light chain polypeptide that comprises a light chain variable region (VL) and a constant region. But while this overall structure is shared amongst antibodies from a wide variety of sources (human, rat, mouse, rabbit), the structure each antibody uses to bind its particular epitope on an antigen is structurally distinct and is formed by a recombination event that results in high variability at the amino acid sequence level. By the time the invention was made, 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, cited on IDS filed 4/13/2026). Chimeric antibodies comprise the heavy and light chain variable regions of a rodent antibody linked to human constant regions and preserve the entirety of the VH and VL of the parent antibody. Id. at 1619-20. 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. Almagro provides a detailed discussion regarding various methods of humanization, including rationale design approaches and empirical approaches based on random screening. Almagro, Sections 4 and 5.
Overall, at the time the invention was made, the level of skill for preparing antibodies and then selecting those antibodies with desired functional properties was high. However, even if a selection procedure was, at the time of the invention, sufficient to enable the skilled artisan to identify antibodies with the recited functional properties, the written description provision of 35 U.S.C § 112 is severable from its enablement provision. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336 (Fed. Cir. 2010); see also Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1876 (Fed. Cir. 2011) (“The fact that a fully-human antibody could be made does not suffice to show that the inventors of the '775 patent possessed such an antibody.”) Absent the conserved structure provided by all six CDRs in the context of appropriate VH and VL framework sequences, the skilled artisan generally would not be able to visualize or otherwise predict, a priori, what an antibody with a particular set of functional properties would look like structurally.
MPEP § 2163 states that 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. Therefore, claims which do not define the antibodies with 100% identity to specific variable or CDR sequences or do not defined all 6 CDR regions or both VH and VL in one claim, are rejected for not adequately providing written description for the entire genus instantly claimed. Furthermore, it is also well established in the art that the formation of an intact antigen-binding site generally requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs which provide the majority of the contact residues for the binding of the antibody to its target epitope. 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 parent 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. 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 1982 Vol 79 page 1979, cited on IDS filed 4/13/2026). 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. MacCallum et al. J. Mol. Biol. (1996) 262, 732-745 cited on IDS filed 4/13/2026, analyzed many different antibodies for interactions with antigen and state that although CDR3 of the heavy and light chain dominate, a number of residues outside the standard CDR definitions make antigen contacts (see page 733, right col) and non-contacting residues within the CDRs coincide with residues as important in defining canonical backbone conformations (see page 735, left col.). Pascalis et al. (The Journal of Immunology (2002) 169, 3076-3084, cited on IDS filed 4/13/2026) demonstrate that grafting of the CDRs into a human framework was performed by grafting CDR residues and maintaining framework residues that were deemed essential for preserving the structural integrity of the antigen binding site (see page 3079, right col.). Although abbreviated CDR residues were used in the constructs, some residues in all 6 CDRs were used for the constructs (see page 3080, left col.). The fact that not just one CDR is essential for antigen binding or maintaining the conformation of the antigen binding site, is underscored by Casset et al. (BBRC 2003, 307:198-205, cited on IDS filed 4/13/2026), which constructed a peptide mimetic of an anti-CD4 monoclonal antibody binding site by rational design and the peptide was designed with 27 residues formed by residues from 5 CDRs (see entire document). Casset et al. also states that although CDR H3 is at the center of most if not all antigen interactions, clearly other CDRs play an important role in the recognition process (page 199, left col.) and this is demonstrated in this work by using all CDRs except L2 and additionally using a framework residue located just before the H3 (see page 202, left col.). Vajdos et al. (J. Mol. Biol. (2002) 320, 415-428, cited on IDS filed 4/13/2026), additionally state that antigen binding is primarily mediated by the CDRs more highly conserved framework segments which connect the CDRs are mainly involved in supporting the CDR loop conformations and in some cases framework residues also contact antigen (page 416, left col.). Chen et al. (J. Mol. Bio. (1999) 293, 865-881, cited on IDS filed 4/13/2026) describe high affinity variant antibodies binding to VEGF wherein the results show that the antigen binding site is almost entirely composed of residues from heavy chain CDRs, CDR-H1, H2, H3 (page 866). Wu et al. (J. Mol. Biol. (1999) 294, 151-162, cited on IDS filed 4/13/2026) state that it is difficult to predict which framework residues serve a critical role in maintaining affinity and specificity due in part to the large conformational change in antibodies that accompany antigen binding (page 152 left col.) but certain residues have been identified as important for maintaining conformation. Padlan et al. (PNAS 1989, 86:5938-5942, cited on IDS filed 4/13/2026) described the crystal structure of an antibody-lysozyme complex where all 6 CDRs contribute at least one residue to binding and one residue in the framework is also in contact with antigen. Lastly, Lamminmaki et al. (JBC 2001, 276:36687-36694, cited on IDS filed 4/13/2026) describe the crystal structure of an anti-estradiol antibody in complex with estradiol where, although CDR3 of VH plays a prominent roll, all CDRs in the light chain make direct contact with antigen (even CDR2 of VL, which is rarely directly involved in hapten binding).
Therefore, the art has established that the epitope or antigen sequence does not provide any information about the antibody paratope sequence structure that binds to it, or provide information as to what epitope residues the antibody will bind. The instant claims identify the claimed antibody by function only or by function + partial CDR sequence structure in order for one to readily envision the claimed genus of PRAME binding TCR variants encompassed by the claims. Given the lack of sufficient representative examples to support the full scope of the claimed antibodies, and lack of reasonable structure-function correlation with regards to the unknown sequences in the CDRs that provide specific binding function, the present claims lack adequate written description.
Applicants are invited to amend the claims to recite the” preferentially expressed antigen in melanoma (PRAME)” antigen and require 100% identity to the recited six SEQ ID NOs or define specific amino acid substitutions within the CDR regions to obviate this rejection.
Conclusion
Claims 1, 3-12, 19-21, 24 are rejected.
Claims 2, 13-18, 22, 23, 25 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
The closest prior art made of record and not relied upon is Alten et al. (WO2018/172533, cited on IDS filed 11/16/2023). Alten et al. teaches T cell receptor molecules which bind to PRAME, however Alten et al. does not teach the specific CDR sequences instantly claimed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MEERA NATARAJAN whose telephone number is (571)270-3058. The examiner can normally be reached M-F 9AM - 5PM.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, JULIE WU can be reached on 571-272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/Meera Natarajan/Primary Examiner, Art Unit 1643
Prosecution Insights