DETAILED ACTION
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 .
Priority
The claims have priority to 62821257, filed 3/20/2019.
Information Disclosure Statement
The IDSs filed 9/17/21 and 11/30/22 have been considered and initialed copies of the PTO-1449 are enclosed.
Drawings
The drawings filed 9/17/21 are objected to because Figures 2 and 3 A-C are incomplete. The lower right corner of each figure has
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168
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Thus, it appears that SEQ ID NO: are missing.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
There are two occurrences on page 87.
Claim Objections
Claim 27 is objected to under 37 CFR 1.75 as being a substantial duplicate of claim 24. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
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.
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 1-30 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 terminology “human-like” in the claims renders the claims vague and indefinite. What is meant by “human-like”?
The use of the term “optionally” renders the claims vague and indefinite. Since applicant uses this term numerous times and uses the term one or more times in a single claim and since the many, many alternatives after the word “optionally” are varied, it is the Examiner’s position that this term introduces ambiguity into the claim. MPEP 2173.05(h)(II).
In claims 10-13, applicant uses the term “derived”. This term renders the vague and indefinite because it is not clear what or how the domain is “derived”. Is the domain derivatized? If so, with what or how?
Claim 18 is confusing because it states “identical to the amino acid sequence set forth in SEQ ID NO: 260”. SEQ ID NO. 260 is a nucleic acid sequence and not an amino acid sequence.
The use of the term “and/or” in claim 18 in combination with the multiple “optionally” renders the claim confusing. It simply is not clear what applicant is trying to claim in this claim.
In claim 24 and 27, the way applicant has recited the diseases to be treated is confusing especially since applicant has listed cancer twice.
Claim 30 is confusing because it is not clear what “(i-a)” is referring to.
Claim 30 is confusing because it appears to be incomplete. The sentence “a vector containing optionally further comprising” appears to missing terminology (lines 4 and 7).
Claims 1, 5-13 and 15-30 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.
“[T]he purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent specification.’” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.04.
For a claim to a genus, a generic statement that defines a genus of substances by only their functional activity does not provide an adequate written description of the genus. Reagents of the University of California v. Eli Lilly, 43 USPQ2d 1398 (CAFC 1997). The recitation of a functional property alone, which must be shared by the members of the genus, is merely descriptive of what the members of the genus must be capable of doing, not of the substance and structure of the members. The Federal Circuit has cautioned that, for claims reciting a genus of antibodies with particular functional properties (e.g., binding to antigen, high affinity, neutralization activity, competing with a reference antibody for binding), “[c]laiming antibodies with specific properties, e.g., an antibody that binds to human TNF-α with A2 specificity, can result in a claim that does not meet written description even if the human TNF-α protein is disclosed because antibodies with those properties have not been adequately described." Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1875, 1877-78 (Fed. Cir. 2011).
“[A] sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus.” Ariad, 598 F.3d at 1350 (quoting Eli Lilly, 119 F.3d at 1568-69). A “representative number of species” means that those species that are adequately described are representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (“The ’128 and ’485 patents, however, only describe species of structurally similar antibodies that were derived from Joe-9. Although the number of the described species appears high quantitatively, the described species are all of the similar type and do not qualitatively represent other types of antibodies encompassed by the 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 to provide a "representative number” of species.
The “structural features common to the members of the genus” needed for one of skill in the art to ‘visualize or recognize’ the members of the genus takes into account the state of the art at the time of the invention. For antibodies, the Federal Circuit has found that possession of a mouse antibody heavy and light chain variable regions provides a structural "stepping stone" to the corresponding chimeric antibody, but not to human antibodies. Centocor, 97 USPQ2d at 1875 (“[T]he application only provides amino acid sequence information (a molecular description of the antibody) for a single mouse variable region, i.e., the variable region that the mouse A2 antibody and the chimeric antibody have in common. However, the mouse variable region sequence does not serve as a stepping stone to identifying a human variable region within the scope of the claims.”). A chimeric antibody shares the full heavy and light chain variable regions with the corresponding mouse antibody; that is, the structure shared between a mouse and chimeric antibody would generally be expected to conserve the antigen binding activity.
Even if a selection procedure is disclosed that 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, 94 USPQ2d at 1167; Centocor at 1876 (“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.”)
Additionally, “An adequate written description must contain enough information about the actual makeup of the claimed products—“a precise definition, such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other materials,” which may be present in “functional” terminology “when the art has established a correlation between structure and function.” Ariad, 598 F.3d at 1350. But both in this case and in our previous cases, it has been, at the least, hotly disputed that knowledge of the chemical structure of an antigen gives the required kind of structure-identifying information about the corresponding antibodies.” Amgen Inc v. Sanofi 124 USPQ2d 1354, 1361 (Fed. Cir. 2017). “Further, the “newly characterized antigen” test flouts basic legal principles of the written description requirement. Section 112 requires a “written description of the invention.” But this test allows patentees to claim antibodies by describing something that is not the invention, i.e., the antigen. The test thus contradicts the statutory “quid pro quo” of the patent system where “one describes an invention, and, if the law's other requirements are met, one obtains a patent.” Ariad, 598 F.3d at 1345.” Amgen at 1362.
Applicant claims antibodies, binding domains and fragments thereof that bind ADAM12, antibody drug conjugates (ADC) comprising said antibody and CAR comprising binding domains to bind ADAM12. Applicant also claims nucleic acids comprising said antibodies, domains, fragments, ADC and CAR. Applicant also claim cells comprising said CAR and recombinant cells comprising vectors comprising said nucleic acids. Applicant also claims methods of using the antibodies, binding domains and fragments thereof, ADC, CAR, nucleic acids and cells. All of the above are claimed by merely describing the antigen—i.e. ADAM12. Thus, these are solely described in terms of function—i.e binding ADAM12. Claim 9 is included in this rejection because of part (III) which also merely described the antibody solely in terms of function.
The only examples provided in the specification are for antibodies h6E6 and h6C10. However, these two antibodies do not provide a precise definition, such as by structure, formula, chemical name, physical properties, or other properties, of a representative number of species falling within the genus sufficient to distinguish the genus from other materials. Merely describing the antigen provides no information about the antibodies, binding domains and fragments thereof, ADC, CAR, nucleic acids and cells.
It is well established in the art that the formation of an intact antigen-binding site of all antibodies requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs or hypervariable regions, which provide the majority of the contact residues for the binding of the antibody to its target epitope (Paul, Fundamental Immunology, 3rd Edition, 1993, pp. 292-295, under the heading “Fv Structure and Diversity in Three Dimensions”) (PTO-892). 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 (Paul, page 293, first column, lines 3-8 and line 31 to column 2, line 9 and lines 27-30). 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 (PTO-892) (see Section 3 “Antibody Structure and the Antigen Binding Site” and Figure 1). 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. It has long been established that 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. In 1982, Rudikoff et al(Proc. Natl. Acad. Sci. USA 1982 Vol. 79: page 1979) (PTO-892) 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. It is unlikely that humanized antibody, humanized scFv and fragments thereof as defined by the claims, which may contain less than the full complement of CDRs from the heavy and light chain variable regions have the required binding function. Pascalis et al (The Journal of Immunology (2002) 169, 3076-3084) (PTO-892) 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. (2003) BBRC 307, 198-205, (PTO-892) 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.). More recently, D’Angelo et al, Frontiers in Immunology vol. 9 p. 1 (2018) (PTO-892) shows that antibodies bind their targets using diversified loops (CDRs) and, of the 6CDRs, HCDR3 is the most diverse. D’Angelo et al examined one CDR in depth and concluded that HCDR3 generated many different VDJ rearrangements (abstract and entire reference). They conclude “that a specific HCDR3 will only define a particular binding specificity within a very narrow structurally appropriate context: i.e. HCDRs is necessary, but is insufficient to define specific anti-binding properties unless combined with appropriate VL and VL germline genes” (page 8, second column). Thus, binding is highly specific to HCDR3 and VH and VL combinations. A generic disclosure of “antibody” with only one example, does not provide a representative number of examples to show that applicant had possession of the claimed invention at the time of filing.
In view of the aforementioned case law, the state of the art and in view of the lack of a representative number of examples representing the genus of antibodies and fragments thereof, ADC, CAR, nucleic acids and cells, the skilled artisan would not recognize that applicants were in possession of the invention as broadly claimed at the time the application was filed.
Claims 3-4, 9 and 14 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 antibodies, binding domains and fragments that bind ADAM12 and CAR with an ADAM12 binding domain. The antibodies, fragments and binding domains
comprise SEQ ID NO. 131, 135, 141 and 145 and sequences with at least 80% identity to the aforementioned sequences or encoded by SEQ ID NO: 231, 235, 241 and 245 and sequences with at least 80% identity to the aforementioned sequences,
scFv of SEQ ID NO. 139, 140, 149 and 150 and sequences with at least 80% identity to the aforementioned sequences or scFv encoded by SEQ ID NO. 239, 240, 249 and 250 and sequences with at least 80% identity to the aforementioned sequences, or
CAR comprising SEQ ID NO. 171-182 and sequences with at least 80% identity to the aforementioned sequences or CAR encoded by SEQ ID NO. 271-282 and sequences with at least 80% identity to the aforementioned sequences.
While the amino acid sequences of SEQ ID NO: 131, 135, 141, 145, 139-140, 149-150 and 171-182 and amino acid sequence encoded by SEQ ID NO. 231, 235, 241, 245, 239-240, 249-250 and 271-282 are adequately described in the specification as-filed, thereby providing an adequate basis for said sequences; there is insufficient written description as to the identity of said sequences having at least 80% identity to the said sequences that would still maintain the function of the polypeptide. Consequently, the specification does not provide an adequate written description for antibodies containing said sequences having at least 80% identity to the aforementioned sequences.
The specification as filed does not provide adequate written description support for amino acid sequences of SEQ ID NO: 131, 135, 141, 145, 139-140, 149-150 and 171-182 and amino acid sequence encoded by SEQ ID NO. 231, 235, 241, 245, 239-240, 249-250 and 271-282 and having at least 80% identity to the aforementioned sequences. The scope of the claim includes numerous structural variants and the genus is highly variant because a significant number of structural differences between genus member is permitted. The specification does not describe any members of the claimed genus by complete structure. Brown et al (J. Immunol. 1996 May; 156(9):3285-3291 at page 3290 and Tables 1 and 2) (PTO-892) describes how a one amino acid change in the VH CDR2 of a particular antibody was tolerated whereas, the antibody lost binding upon introduction of two amino acid changes in the same region. Furthermore, M229 of Brown et al (in Table 1) shows conservative substitutions of gly for ser and pro for ala (and these are defined as conservative substitutions by applicant on page 28, lines 25+ of the specification. The use of these two conservative substitutions results in loss of binding. Thus, merely because a substitution is “conservative” this does not mean that functionality of the antibody/peptide is retained. Vajdos et al (J. Mol. Biol. 2002, Jul 5;320(2); 415-428) (PTO-892) at page 416 teach that amino acid sequence and conformation of each of each of the heavy and light change CDRs are critical in maintaining the antibody binding specificity and affinity which is characteristic of the parent immunoglobulin.
Adequate written description requires more than a mere statement that it is part of the invention. The sequence itself is required. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
Therefore, only SEQ ID NO: 131, 135, 141, 145, 139-140, 149-150 and 171-182 and 231, 235, 241, 245, 239-240, 249-250 and 271-282 meet the written description provision of 35 U.S.C. 112, first paragraph. Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the written description inquiry, whatever is now claimed. (See page 1117.) The specification does not clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed. (See Vas-Cath at page 1116.). Consequently, Applicant was not in possession of the instant claimed invention. See University of California v. Eli Lilly and Co. 43 USPQ2d 1398.
Claims 6, 10-13 and 18 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 antibodies or CAR to ADAM12.
Claim 6 is directed to a Fc region that is at least 80% identical to a human Fc and wherein the Fc binds its receptor.
Claim 10 is directed to the TM domain of CAR wherein the TM domain is (I) derived from the TM region, or a membrane-spanning portion thereof, of a protein selected from CD28, CD3e, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD45, CD64, CD80, CD86, CD134, CD137, CD154, TCRa, TCRb, and CD3z, (II) optionally derived from the TM region of CD28, or a membrane-spanning portion thereof, and (III) further optionally comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to the amino acid sequence: (i) set forth in SEQ ID NO: 161; or (ii) encoded by SEQ ID NO: 261. This claim reads on parts of the TM domain and TM domain with at least 80% identity to SEQ ID NO. 161 or 261.
Similarly, claim 11 is directed to the ICS domain (I) derived from a cytoplasmic signaling sequence, or a functional fragment thereof, of a protein selected from the group consisting of CD3z, a lymphocyte receptor chain, a TCR/CD3 complex protein, an Fc7receptor (FcR) subunit, an IL-2 receptor subunit, FcRg, FcRb, CD3g, CD3d, CD3e, CD5, CD22, CD66d, CD79a, CD79b, CD278 (ICOS), FceRI, DAP 10, and DAP12, (II) optionally derived from a cytoplasmic signaling sequence of CD3z, or a functional fragment thereof, and (III) further optionally comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to the amino acid sequence: (i) set forth in SEQ ID NO: 162; or (ii) encoded by SEQ ID NO: 262. This reads on fragments of ICS domain and ICS domain with at least 80% identity to SEQ ID NO. 162 and 262.
Similarly, claim 12 is directed to the hinge domain and hinge domain with at least 80% identity to SEQ ID NO. 163 or 263.
Similarly, claim 13 is directed to the CS domain and fragments of the CS domain and CS domain with at least 80% identity to SEQ ID NO. 164 or 264.
Similarly, claim 18 is directed to the leader sequence with at least 80% identity to SEQ ID NO. 260, T2A sequence with at least 80% identity to SEQ ID NO. 269 and a trCD19 sequence with at least 80% identity to SEQ ID NO. 170.
To summarize, the language that necessitated this written description rejection is ”membrane-spanning portion”, “functional fragment” and “at least 80%-99% identity to”. There is insufficient written description as to the ”membrane-spanning portion”, “functional fragment” and sequences having at least 80-99% identity to the SEQ ID NO. in the claims and that would still maintain the function of the polypeptide (ie. binding Fc, functioning as a TM domain, ICS domain, hinge, CS domain or as a leader sequence). Consequently, the specification does not provide an adequate written description of an ”membrane-spanning portion”, “functional fragment” and having at least 80-99% sequence identity to the specified SEQ ID NO.
Polypeptides having diverse functions are encompassed by the phrase portion, fragment and 80-99% identity. Thus a broad genus having potentially highly diverse functions is encompassed by the aforementioned phrases and conception cannot be achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method. For example, Skolnick et al. (Trends in Biotech., 18(1):34-39, 2000) (PTO-892) teach that the skilled artisan is well aware that assigning functional activities for any particular protein or protein family based upon sequence homology is inaccurate, in part because of the multifunctional nature of proteins (e.g., Abstract and Sequence-based approaches to function prediction, page 34). Even in situations where there is some confidence of a similar overall structure between two proteins, only experimental research can confirm the artisan’s best guess as to the function of the structurally related protein (see in particular Abstract and Box 2). Adequate written description requires more than a mere statement that it is part of the invention. The sequence itself is required. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
There is no teaching in the specification regarding which 20% of the amino acids can be varied while retaining the ability of the peptide maintain the claimed function or as to which portion or fragment will retain the function of the protein. Further, there is no art-recognized correlation between any structure (other than the full length proteins and specified SEQ ID NO.) and the associated function on which those of ordinary skill in the could predict which amino acids can vary from the specified SEQ ID NO. or full length proteins with losing activity. Consequently, there is no information about which amino acids can vary from specified SEQ ID NO. or full length proteins in the claimed genus of proteins and still retain the activity.
Therefore, only specified SEQ ID NO. or full length proteins meet the written description provision of 35 U.S.C. 112, first paragraph. Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that Aapplicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the written description inquiry, whatever is now claimed. (See page 1117.) The specification does not clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed. (See Vas-Cath at page 1116.). Consequently, Applicant was not in possession of the instant claimed invention. See University of California v. Eli Lilly and Co. 43 USPQ2d 1398.
Claim 9 is 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 claim is directed to AB domain which “competes” with binding to ADAM12.
In paragraph 441, applicant states that the ability to compete can determined using binding assays and that competition assays are known to the skilled artisan.
While one may be able to assay whether an antibody “competes” with the recited monoclonal antibody, it is apparent that the degree to which an antibody competes with another antibody is a relative or subjective expression, and the requisite degree to which the claimed antibody competes with a monoclonal antibodies cannot be ascertained from the disclosure.
Contrary to the assertion in the specification that such a binding assay determines whether two antibodies bind to the same antigenic determinant (i.e., epitope), competing antibodies do not necessarily bind the same epitopes. For example, “competing” antibodies may bind spatially overlapping but discrete epitopes. Simply because two antibodies cannot simultaneously occupy the same space, such an antibody, once bound to the antigen, sterically hinders or blocks binding of another such antibody. As another example, a “competing” antibody might not necessarily bind to the same epitope of an antigen as another antibody, if one of the antibodies induces conformational shifts in the three-dimensional structure of the antigen upon binding, which prevents binding of the other antibody to the antigen because the epitope to which it would otherwise bind is unrecognizable as a consequence of the structural change.
In addition, it is recognized that the degree of binding of an antibody, which is observed in the exemplified competitive binding assay, will depend upon the concentration of the detectably labeled antibody and the unlabeled competing antibody. Typically, the higher the concentration of the unlabeled competitor, the lower the percentage of binding of the labeled antibody. So, at high concentrations, any antibody might be deemed capable of “competing” for binding to an antigen with any other antibody, regardless of whether or not the different antibodies bind to the same, or even overlapping epitopes.
George et al. (Circulation. 1998; 97: 900-906) (PTO-892), for example, describes different antibodies, which do not bind to the same epitope of an antigen, but are nevertheless capable of competing with one another for binding to the antigen; see entire document (e.g., page 903, paragraph bridging columns 1 and 2). More particularly, George et al. describes three antibodies, which bind decidedly different, non-cross-reactive epitopes on b2GPI; yet, George et al. teaches each is able to “compete” by a measurable extent with any of the others for binding to the antigen (page 903, paragraph bridging columns 1 and 2). For example, George et al. teaches monoclonal antibody ILA-4 competed with itself for binding to the antigen (% inhibition = 90 ± 11%), but George et al. discloses, despite its binding a non-overlapping epitope, monoclonal antibody ILA-1 also “competed”, albeit with monoclonal antibody ILA-4 for binding to the antigen (% inhibition = 9 ± 4%).
Accordingly, George et al. illustrates the capricious and arbitrary nature of determinations that different antibodies bind to the same or different epitopes, which are based upon the results of competitive binding assays, such as the assay exemplified in the specification.
Claims 24-25, 27 and 29 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 methods of treating a subject having a cancer which expresses ADAM12, does not reasonably provide enablement for methods of treating a subject having a cancer which does NOT expresses ADAM12 or for the treatment of diseases other than ADAM expressing cancers. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
Applicant claims and discloses methods of treating a subject having a variety of different diseases using the claimed products. While there is sufficient evidence to show enablement of treatment of cancer which express ADAM12, there is no evidence to enable the treatment of cancers which do not express ADAM12 or for the treatment of diseases other than ADAM expressing cancers.
Treatment of cancer which express ADAM12
It is generally accepted that an antibody must bind its antigen to mediate an effect. Further, for those antibodies that mediate their effect by cytotoxic mechanisms, the art recognized that the antibody must still attach to the tumor cell by binding its antigen and only then does the Fc domain trigger the immune-mediated effect. For example, Strome et al., The Oncologist, 2007; 12:1084-95 (PTO-892) notes that “[i]n ADCC [antibody-dependent cellular cytotoxicity], an IgG antibody first binds via its antigen-binding site to its target on tumor cells, and then the Fc portion is recognized by specific Fc gamma receptors (FcgR) on effector cells.” Strome, p. 1087 “ADCC”.
The importance of high levels of antigen expression in obtaining responsiveness to antibody therapy is underscored by clinical studies in breast cancer. By 2006, the skilled artisan understood that only those patients with tumors overexpressing the HER2 receptor were good candidates for treatment with an anti-HER2 receptor antibody. For example, Brand et al., Anticancer Res. 2006; 26:463-70 (PTO-892), note that "HER2 overexpression is predictive of the effectiveness of treatment by the monoclonal antibody Herceptin® (trastuzumab), which specifically targets the HER2 receptor.” Brand, p. 466, first paragraph.
Treatment of diseases other than ADAM expressing cancers
Applicant claims the treatment of fibrosis, autoimmunity, a cardiovascular condition, an allergic condition, a respiratory disease, a nephropathy, a neural disease, a muscular disease, a liver disease, metabolic syndrome, infection, or an inflammatory disorder. In support of this, applicant has enabled the treatment of cancers which express ADAM12.
Johnson et al, Cancer Treatment Reviews vol. 2 p. 1 (1975) (PTO-892) discloses that one single compound cannot treat all types of cancers (Table 2). Since one single compound cannot treat all types of cancers, a skilled artisan would understand that one single compound cannot treat different types of diseases. This is especially true since the different diseases have different etiologies.
Thus, in view of the above and in view of the state of the art, it is the Examiner’s position that one of skill in the art would require undue experimentation to make and/or use the claimed invention.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claim 25 is rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more. Claim(s) 25 is/are directed to a judicial exception. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because it does not read on statutory patentable subject matter.
Claim 25 is drawn to a non-statutory method having a "natural principle" as a limiting element or step without reciting additional elements/steps that integrate the natural principle into the claimed invention such that the natural principle is practically applied, and are sufficient to ensure that the claim amounts to significantly more than the natural principle itself.
While it is clear anti-ADAM12 treatment is administered once the artisan has measured the expression level of ADAM12 and the patient is an ADAM12 over-expresser, it is clear the method of treatment is integrated into the natural relationship between assessing the over-expression of ADAM12. Limitations that are indicative of integration into a practical application can include the particular application of a natural law to effect a particular treatment or prophylaxis for a disease or medical condition. See, e.g., VandaPharms. Inc. v. West-Ward Pharms. Int’l Ltd., 887 F.3d 1117, 1134—35 (Fed. Cir. 2018).
However, the "natural principle" is still present in claim 25 wherein after measuring and determining ADAM12 over-expression and there is no over-expression then there is no subsequent treatment and, therefore, the claims do not practically apply this the natural relationship. This embodiment does not direct application of anti-ADAM12 treatment to treat any particular disease or integrate the law of nature. In other words, if a certain condition precedent is not met, the additional step of administering treatment is not performed.
A claim that focuses on use of a natural principle must also include additional elements or steps to show that the inventor has practically applied, and added something significant to, the natural principle itself. See Mayo, 101 USPQ2d at 1966. Recited elements such as “assaying”, “comparing” and “determining” based on the natural principle impose no meaningful limit on the performance of the claimed invention. Patents cannot be obtained on subject matter identified by the courts as being exempted from eligibility (i.e., laws of nature, natural phenomenon, and abstract ideas). Further, the active method steps are conventional and routine in the art for the reasons stated above and the claims do not amount to significantly more than the recited natural principle. The claims do not "practically apply" the natural principle; rather, the claims read on gathering data and "simply inform" the natural principle to one performing routine active method steps and do not amount to significantly more than the natural principle itself. See the 2019 Revised Patent Subject Matter Eligibility Guidance, Federal Register (https://www.federalregister.gov/documents/2019/01/07/2018-28282/2019-revised-patent-subject-matter-eligibility-guidance) and/or FDsys.gov.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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, 5-7, 16, 19, 20, 22-24 and 26-29 is/are rejected under 35 U.S.C. 102a1 as being anticipated by Peduto et al WO 2017/134265 (IDS of 11/30/22).
The reference discloses methods of administering immunoconjugates comprising a monoclonal antibody or fragment that binds ADAM12 in combination with a second anti-tumor compound (antibody, modified immune cell, drug, etc) for the treatment of cancers (summary, abstract, para 8, 10-12, 23, 39-45 and entire reference). The ADAM monoclonal antibody has ADCC or CDC activity (para 25). The reference discloses monoclonal antibodies, fragment and conjugates directed to ADAM 12 wherein the immunoconjugate is linked to a toxic molecule (para 41, 72-84). The anti-ADAM12 antibodies are made recombinantly using genetic engineering methods including standard recombinant DNA techniques (para 54 and 65). The monoclonal antibodies can be humanized or chimeric (para 64) and fragments include Fab and F(ab’)2 (para 63), sdAb, plural specificity antibodies and fully synthetic antibody-like molecules (para 66-67). The second agent can be tumor associate antigens, immune adjuvants, immune modulators, small molecules, modified immune cells, cytokines, anti-angiogenic therapies, immune checkpoint blockage (i.e. antibodies), viruses and nucleic acid vectors, chemotherapy agents (para 93-129). The cancers treated include prostate cancer, colorectal cancer, lung cancer, breast cancer, liver cancer, bladder cancer, pancreatic cancer, etc (para 133-134).
With respect to claim 5, the disclosure of “plural specificity antibodies” reads on this claim because claim 5(ii) reads on bispecific antibody wherein the second antigen is other than ADAM12. The specificity for CD3, NKG2D, 4-1BB and FcR is optional and not required in the claim.
With respect to claim 6, the disclosure that the ADAM monoclonal antibody has ADCC or CDC activity means that it has an Fc region.
With respect to claim 16, since the antibodies are made recombinantly using genetic engineering methods including standard recombinant DNA techniques, this reads on nucleic acid encoding the antibody.
With respect to claims 19 and 20, since the antibodies are made recombinantly using genetic engineering methods including standard recombinant DNA techniques, it is standard that the recombinant methods involve vectors and cells. Additionally, in claim 20, the types of cells are “optional” and not required in the claim.
With respect to claim 22, the reference discloses that the antibodies are made recombinantly using genetic engineering methods including standard recombinant DNA techniques and this requires a cell. The second cell in the claim is optional.
With respect to claim 26 and 28, the reference and the claims are administering the same compound to the same patient population therefore, it is inherent that effects are the same. Specifically, the effects are that the administration of the compound in the reference would stimulate an immune response and expand a population of cells in the patient.
Claim(s) 1, 6 and 23-28 is/are rejected under 35 U.S.C. 102a1 as being anticipated by Peduto et al CA 2 676 946 (PTO-892).
Peduto et al discloses determining the expression levels of ADAM12 in a sample. (page 3, lines 4-15 and page 12-13 and entire reference). The reference also discloses methods of treating fibrosis using ADAM12 inhibitor in a pharmaceutical composition, where the inhibitor can be an antibody (page 4, lines 15-18, page 7-9).
With respect to claim 6, since the reference discloses antibody, and not antibody fragment, it is the Examiner’s position that the antibody has an Fc.
With respect to claim 25, if there is no over-expression then no ADAM12 antibody is administered. The reference discloses the determining the expression levels of ADAM12 in a sample.
With respect to claim 26 and 28, the reference and the claims are administering the same compound to the same patient population therefore, it is inherent that effects are the same. Specifically, the effects are that the administration of the compound in the reference would stimulate an immune response and expand a population of cells in the patient.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1, 8, 10-11, 13, 16-17, 19-24, 26-28 and 30 is/are rejected under 35 U.S.C. 103 as being unpatentable over Xiao et al WO 2019/140100 (published 7/18/2019, priority to 7/11/2018) (PTO-892).
Xiao et al discloses CAR molecules to ADAM12 (Table 1 and claims 1-2) wherein the CAR comprising an extracellular domain, which is an antigen binding domain or fragments such as scFv, one or more co-stimulatory and signaling domains of ICOS, CD2 and CD3zeta (reads on applicant’s ICS and CS), a transmembrane domain of CD28 of 4-1BB molecule (para 110-118). The reference discloses cells comprising nucleic acids and vectors of the CAR (para 125-126). The reference discloses the in vitro cell preparation of the cells (reads on applicant’s claim 30, generating a cell comprising CAR), methods of using the cells to enhance T cell expansion in a subject (reads on applicant’s claim 28) and methods of inducing a T cell response in a subject using said cells (reads on applicant’s claim 26) (para 127-139, 166, 169, 179). The reference also discloses pharmaceutical compositions comprising said CAR (para 174-176) and administering the compositions to a subject for the treatment of cancers (para 2 and 177+). Also see para 203 and entire reference.
The only difference between the reference and the instant invention is that the reference does not specifically disclose the CAR to ADAM12.
However, in view of the clear disclosure of CAR to ADAM12 (claims 1-2 of reference) and the clear disclosure of the CAR components and cells comprising nucleic acids and vectors of the CAR, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to make these CARs. Additionally, in view of the clear disclose to use the CARs in methods of using the cells to enhance T cell expansion in a subject and methods of inducing a T cell response in a subject using said cells, it would have been obvious to do so.
Claim 1 is included in this reference because the CAR comprises an antigen binding fragment of ADAM12 and the limitations after the word “optionally” are merely optional.
With respect to claim 8, it is noted that parts (d)-(e) of the CAR are optional.
With respect to claims 10-11 and 13, it is noted that parts (II) and (III) are optional.
With respect to claim 20, the types of cells are “optional” and not required in the claim.
Claim(s) 1, 8, 10-13, 16-17, 19-24, 26-28 and 30 is/are rejected under 35 U.S.C. 103 as being unpatentable over Xiao et al WO 2019/140100 (published 7/18/2019, priority to 7/11/2018) (PTO-892) in view of Finer et al US 2015/0329640 (PTO-892).
Xiao et al has been discussed above.
The only difference between the reference and the claimed invention is the hinge being derived from CD28.
Finer et al discloses the CAR with a hinge of CD28 are known in the art (para 10, 71 and entire reference).
Since Finer et al discloses the CAR with a hinge of CD28 are known in the art and since Xiao et al discloses CAR molecules, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use CD28 as the hinge in the CAR of Xiao et al.
It is noted that part (II) in claim 12 is optional.
Free of art
Claims 2-4, 9 and 14 are free from the art of record because the prior art does not teach or suggest antibodies which comprise (i) CDRs of SEQ ID NOs: 132, 133, 134, 136. 137, and 138 or (iii) CDRs of SEQ ID NOs: 142, 143, 144, 146, 147, and 148. The prior art does not teach or suggest antibodies which comprise (ii) CDRs encoded by SEQ ID NOs: 232, 233, 234, 236. 237, and 238 or (iv) CDRs encoded by SEQ ID NO: 242, 243, 244, 246, 247, and 248. Thus, SEQ ID NO. 131, 135, 231, 235, 141, 145, 241 and 245 are also free from the art of record. Additionally, SEQ ID NO. 139-140, 149-150, 239-240 and 249-250 are also free from art because of the reasons set forth above. Additionally, SEQ ID NO. 171-182 and 271-282 are also free from art because of the reasons set forth above.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SHEELA J HUFF whose telephone number is (571)272-0834. The examiner can normally be reached M-Th 6:30am to 4pm Eastern Time.
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/Sheela J. Huff/Primary Examiner, Art Unit 1643
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