DETAILED ACTION
The claim amendments filed 11/08/2024 are acknowledged and entered into the record.
Accordingly, Claims 1, 5, 7, 9, 11, 13, 14, 16, 17, 19, 25, 29-31, and 33 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.
Claims 7, 11, 13, 16, 19 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.
The Claims recite “depicted” in SEQ ID NOs. It is unclear whether the term “depicted” requires the entire CDR/VH/VL regions to be present without any alterations. Applicant is invited to amend the claim to recite for example “CDR-H1 comprising SEQ ID NO:” or “VH regions comprising SEQ ID NO:” to indicate 100% of the recited SEQ ID NO is comprised by the antibody.
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.
Claim 29 is 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 a method of treating and/or ameliorating a tumor or cancer, does not reasonably provide enablement for “preventing” a tumor or cancer. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The nature of the invention is such that the composition of the instant claims must have a therapeutic benefit and be able to prevent a tumor from forming in a patient, much like a vaccine. The art teaches that a vaccine must be prophylactic (Stedman's Medical dictionary, 2000, lines 1-3). The specification does not provide any teachings of the prophylaxis of cancer, how to determine the individuals who will develop a particular cancer, nor how to effectively prevent said particular cancer type before occurrence. Thus, one of skill in the art would not be able to use the composition of the invention as a preventing vaccine without undertaking to determine how to select for individuals who will develop a particular cancer type before the said cancer occurs in the individual. An effective therapeutic protocol for the treatment or prevention of the formation of a tumor is subject to a number of factors, which enter the picture beyond simply the administration of a bispecific antibody which binds CDH3 and CD3.
Predicting whether an individual is at risk for developing cancer is a very unpredictable art. Several factors play a role including, genetic makeup, environmental factors, age, diet, etc. For example Apantaku et al. (Breast cancer diagnosis and screening, American Family Physician 2000) reveals that most women with breast cancer have no identifiable risk factors. Although drawn to breast cancer it is relevant to the unpredictability in the art of identifying patients at risk for developing cancer. The reference further teaches that women who have pre-menopausal first-degree relatives with breast cancer have a three- to four fold increased risk of developing breast cancer than women who do not. The risk factor of their having second-degree relatives with breast cancer has not been quantified. The reference further teaches that genetic testing is controversial and raises issues about the reliability of tests and the use made of test results. A woman who tests negative for a particular mutation may still be at risk for developing breast cancer from a sporadic mutation or a preexisting unidentified mutation. False negative results are also possible. The reference then goes on to detail factors that may be involved with increased risk of breast cancer and suggests change of diet may alter personal risk factors. Although one group is identified as being at increased risk, there is no teaching of how or when to begin an intervention protocol. A review of Martin et al (Journal of the National Cancer Institute, Vol.92, No. 14: pp.1126-1135, July 19, 2000) reveals that it is hoped that identification of genetic and environmental factors that contribute to the development of breast cancer will enhance prevention effects. The reference reviews the state of the art of breast cancer genetic components of susceptibility to breast cancer from the standpoint of both human genetics and rat models (see abstract). The reference specifically states that despite numerous studies published to date, the role of modifier genes in breast cancer susceptibility remains to be elucidated. The resolution of ambiguous results will require further carefully designed studies with sufficient sample sizes to detect small effects. The reference concludes that great strides have been made in determining the disease etiology but that further investigation is necessary and that these studies will be crucial to evaluate the importance of new genes involved in breast cancer etiology so that scientists can define better therapies and cancer prevention (p. 1132, col 1) Finally, there is no teaching of how or when to begin an intervention protocol. It is clear from the teachings of this reference that the art of identifying an individual at risk for malignant growth is a developing but as yet undeveloped art. The reference provides no guidance on how to determine which patients are at risk or when to administer treatment in order to inhibit the malignant cell growth for which the individual is at risk.
These references clearly point to the undeveloped nature of the art of reading cancer markers for the assessment of the probability of developing cancer and do not teach what interventions would have a reasonable expectation of success nor teach when or how those protocols should be administered.
Therefore, given the unpredictability of in vivo cancer treatment, the unpredictability of identifying patients that are in need of cancer prevention, one of skill in the art would not know how to use the invention as claimed. Thus, undue experimentation would be required to perform the claimed method of prevention comprising administering a bispecific CDH3xCD3. Applicant is advised to amend the claims to a method of treating and/or ameliorating, not preventing, a tumor or cancer.
Claims 1, 5, 14, 17, 25, 29-31, and 33 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 pre-AIA 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 bispecific antibody construct comprising a first human binding domain which binds to an epitope cluster of human CDH3 on the surface of a target cell and comprising a second binding domain which binds to human CD3 on the surface of a T cell, wherein the epitope cluster of human CDH3 is comprised within amino acid positions 328-363 (SEQ ID NO: 35) of human CDH3 comprising SEQ ID NO: 1, or an epitope comprising amino acids 404-440 (SEQ ID NO: 390) of human CDH3 comprising SEQ ID NO: 1 and methods of treatment comprising administering said antibody. The instant claims define the epitope the bispecific antibody recognizes without defining a structure to function correlation. The claims are further drawn to only having partially defined CDR sequences and not a full set of 3 CDRs from the heavy chain paired with 3 CDRs from the light chain.
The instant specification only makes/describe specific CDH3xCD3 binding bispecific antibodies targeting the recited epitopes which can be used diagnostically or therapeutically, however the CDR sequences of one antibody do not predict the CDR sequence/structure of any and all other antibodies with the recited specific epitope binding yet to be discovered that function as claimed. There is no shared structure among the antibodies. The instant application does not provide adequate written description for any and all CDH3 antibodies which binds to the recited epitope regions yet to be discovered, even those that bind known epitopes on CDH3. Furthermore, although screening applications are well known in the art to identify CDH3 binding antibodies, screening is only a wish or plan for the future invention of undiscovered, unknown antibodies (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). Applicants have not described every species of bispecific antibodies that functions as claimed to adequately describe the entire genus used in the method of treatment instantly claimed. Based on the disclosed antibody sequences, one could not readily envision or predict the CDR sequences of any and all other future, undiscovered CDH3xCD3 bispecific antibodies that can function 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. A description of a genus of antibodies may be achieved by means of a recitation of a representative number of antibodies, defined by sequence, falling within the scope of the genus or of a recitation of structural features common to the members of the genus, which features constitute a substantial portion of the genus. The written description requirement can be met by showing that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics ....i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics.
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. The specifically defined antibody sequences claimed or disclosed in the specification are not representative of nor predictive of any and all other antibody sequences for the broadly claimed genus. There is no common/shared structure among the antibodies having the claimed binding function. However, the instant specification does not describe sufficient representative examples to support the full scope of the claims. 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 the instant case, the claims broadly encompass a large scope of variant antibodies that function as claimed, however the CDR sequences of one antibody do not predict the CDR sequence/structure of any and all other antibody variants that function as claimed. Applicants have not established any reasonable structure-function correlation with regards to the antibody sequences required to bind an epitope within aa291-363 of SEQ ID NO: 36, aa291-327 of SEQ ID NO:34, aa328-363 of SEQ ID NO: 35, and aa404-440 of SEQ ID NO: 290 for the entire genus instantly claimed because the exemplary antibodies do not share sequence homology for the function of binding the recited epitopes and its intended use for treatment. Therefore, claims which do not define the antibodies with 100% identity to specific variable or CDR sequences or both VH and VL variable region sequences, 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). 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, 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) 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), 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), 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) 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) 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) 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) 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).
In view of the prior art teaching mentioned above, one of skill in the art would conclude that applicant was not in possession of the structural attributes of a representative number of species possessed by the members of the genera of antibodies recited in the instant claims. One of skill in the art would conclude that the specification fails to disclose a representative number of species to describe the claimed genera.
Applicant is invited to amend the claims to recite either both VH and VL sequences or all 6 CDR sequences (3 from the light chain and 3 from the heavy chain) to obviate this rejection.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 5, 7, 9, 11, 13, 14, 16, 17, 19, 25, 29-31, and 33 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. 11,028,171. Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims and those of US Patent 11,028,171 are both drawn to the same bispecific antibody targeting CDH3 and CD3 having the same CDR/VH/VL sequences. The claims overlap in scope.
Claims 1, 5, 7, 9, 11, 13, 14, 16, 17, 19, 25, 29-31, and 33 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of U.S. Patent No. 11,926,666. Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims are drawn to the same bispecific antibody targeting CDH3 and CD3 having the same CDR/VH/VL sequences and method of treatment as claimed in the method of treatment of US Patent 11,926,666. The claims overlap in scope.
Conclusion
Claims 1, 5, 7, 9, 11, 13, 14, 16, 17, 19, 25, 29-31, and 33 are rejected.
No claim is allowed.
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/Meera Natarajan/Primary Examiner, Art Unit 1643
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