Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Claims 30-45 are now under consideration in the instant Office Action.
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 32 and 33 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.
Instant claims 32 and 33 recite a sequence identifier, SEQ ID NO: 36, in parentheses. It is unclear if the “peptide” listed prior to the parentheses has the same identity as the sequence that follows within the parentheses. Additionally, the use of parentheses in claims are limited to acronymizing terms for future use. Applicant does not appear to be doing this at this iteration.
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 33, 39-40, and 42 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.
Claims 33, 39-40, and 42 are directed to any chimeric antigen receptor comprising an antigen binding domain that binds Lym1. As such, the claim is directed to an antibody defined entirely by function (binding). See MPEP §2163(I)(A) which states:
"The claimed invention as a whole may not be adequately described where an invention is described solely in terms of a method of its making coupled with its function and there is no described or art recognized correlation or relationship between the structure of the invention and its function. A biomolecule sequence described only by a functional characteristic, without any known or disclosed correlation between that function and the structure of the sequence, normally is not a sufficient identifying characteristic for written description purposes, even when accompanied by a method of obtaining the claimed sequence.”
In this case, antibodies generally share certain characteristics such as Fc regions or hinge regions. However, these structures are not correlated with the binding function of the antibody. The hyper variable regions (HVRs), i.e., complementarity determining regions (CDRs) of an antibody, are well established in the art as the portion of the binding region which imparts the specificity of an antibody. However, there is no way to a priori look at an antigen sequence (Lym1) and envisage the combination of six CDRs that will bind that antigen. First, even highly related CDRs may not bind the same target. See for example Kussie (instant PTO-892) who demonstrates that a single amino acid change in the heavy chain of an antibody which binds p-axophenylarsonate (Ars) completely abrogates the ability of the antibody to bind Ars but adds the functionality of binding the structurally related p-azophenylsulfonate (e.g., abstract). Second, even when provided with several related antibodies that bind the desired target, this does not represent the astronomical and potentially unknowable breadth of all possible amino acid sequences which will result in the desired binding properties. This is exemplified by the Court decision in Abbvie (Abbvie v Janssen 759 F.3d 1285 (Fed. Cir. 2014)), where Abbvie developed over 200 antibodies that shared 99.5% identity in the variable regions (p.7) and which bound the target, but in no way allowed one to envisage the unique structure of Centocor’s antibodies which bound the same target but shared only 50% sequence similarity (see table on page 11).
Thus, the art recognizes that the CDRs define the binding properties of an antibody and that even single amino acid changes to this region can completely abrogate the binding specificity of an antibody. As a further example, see Chen et al., 1995 (instant PTO-892) which demonstrates single amino acid changes in the VH CDR2 sequence can increase binding, decrease binding, destroy binding, or have no effect on binding when compared to the wild-type antibody.
See also Koenig 2017 (instant PTO-892), which provides a large mutation analysis study where every amino acid in both variable regions are substituted with every other amino acid. Looking at figure 1 of Koenig, the bottom half of each section (labeled VEGF) relates to the ability of the mutant to bind the original target, with blue meaning a reduced affinity and black meaning a complete loss of binding ability. In VH-CDR2, for example, mutating any given residue to cysteine, which is encompassed by the instant claims, resulted in reduced binding at 12 residues and a complete loss of binding at 5 residues. That is, at 100% of the positions, mutation to cysteine reduced or ablated the antibody’s ability to bind the target. Looking at a specific position, in 100% of the mutations of residue 55, binding was reduced (15/19) or eliminated (4/19). While residues 56-65 appear more tolerant of change, residues 50-55 are generally intolerant of change.
It is appreciated that Koenig is studying one specific antibody and there is no evidence that the instant antibodies would react in the same way. However, this is part of the problem. It is entirely unclear from the specification which residues of Applicant’s CDRs are tolerant or intolerant to change, and whether those tolerant positions are only tolerant to conservative mutations. The fact that some residues might tolerate mutation does not convey to the skilled artisan that Applicant knew which of the claimed residues were tolerant of such, i.e., does not convey that Applicant was in possession of those sequences which are mutated yet preserve the claimed function. In other words, the specification fails to convey possession of an invention commensurate in scope with what is now claimed and therefore fails to meet the written description requirement. Looking at Koenig figure 2A, ~200 mutations in the CDR region of the VH chain completely abrogates any binding. While 2B appears to indicate that the CDRs of VL are more tolerant of change than the heavy chain CDRs, still over half of the mutations reduce binding compared to the parent.
Thus, making changes to the CDR sequence of an antibody is a highly unpredictable process and the skilled artisan could not a priori make any predictions regarding such mutations with any reasonable expectation of success nor envisage the breadth of structurally unrelated CDR combinations that would still possess the required functions.
The specification discloses only three pairs of heavy and light chain immunoglobulin variable domains which comprises SEQ ID NOs: 2, 4, 6, 8, 10, 12. However, as discussed above, without any way to determine how broad the genus of such antibodies are, there is no way to determine if these antibodies represent the full breadth of what is claimed. The disclosure of these specific antibodies would not convey to the artisan that Applicant was in possession of the full genus of all antibodies which possess the required functions nor does it allow the skilled artisan to envisage the specific structure of such antibodies or antigen binding domains of a chimeric antigen receptor.
Further note the decision in Amgen v. Sanofi 2017, where the Court supported previous decisions (Centocor 2011; Abbvie 2014) that defining an antibody solely by what it binds does not satisfy the written description requirement, stating that this would allow patentees to “claim antibodies by describing something that is not the invention, i.e., the antigen”. This decision has precipitated guidance to the Office instructing that the portion of MPEP 2163 regarding the “newly characterized antigen test” (indicating a well-characterized antigen is sufficient to satisfy written description for antibodies which bind that antigen) should no longer be used and that contrary materials should not be relied upon as reflecting the current state of the law.
It is appreciated that certain claims do include at least one pair of sequences, e.g., claim 30 requires SEQ ID NOs: 6 and 8 as comprising the heavy and light immunoglobulin variable domains. Instant claims 33, 39-40, and 42 require a complete antigen binding fragment but retains no specific structure so long as the binding function is retained, nor does it recite an intended antigen target for the chimeric antigen receptor.
However, as above, arbitrarily altering any amino acid in the CDR of an antibody is unpredictable and the specification does not convey possession of any CDRs other than those of the disclosed antibodies. Further, it is well-known in the art that specificity of an antibody stems from the interaction of six CDRs. Moreover, CDRs are not generally recognized as interchangeable, such that using one CDR from one antibody would not be reasonably expected to confer the same binding properties or even the same binding target when combined with two to five CDRs from other antibodies. For example, WO 2008068048 (instant PTO-892) discloses an antibody with a heavy chain comprising three CDRs (SEQ ID NO: 2) that binds secreted aspartyl protease from Candida sp. US 20170355756 (instant PTO-892) describes the same three CDRs in the heavy chain (C10-VH3) combined with a different light chain that binds human TDP-43. There is no evidence in the instant specification that a single CDR placed in the context of two to five other CDRS, regardless of what those other CDRs are, would result in the required function, nor that a single chain is correlated to the required function when combined with any other chain. As such, the specification fails to set forth a structure-function correlation sufficient to claim all possible antibodies defined by function and one-three CDRs or alterations thereof.
As such, the disclosure of three pairs of immunoglobulin variable domain sequences does not convey possession of other antibodies with the same binding properties; possession of the precisely defined sequences of six CDRs or immunoglobulin variable domain sequences are required.
With respect to product claims 33, 39-40, and 42, it is recognized that information which is well known in the art need not be described in detail in the specification (MPEP §2163(II)(A)(2)). See, e.g., Hybritech, Inc. v. Monoclonal Antibodies, Inc., 802 F.2d 1367, 1379-80, 231 USPQ 81, 90 (Fed. Cir. 1986). However, sufficient information must be provided to show that the inventor had possession of the invention as claimed. MPEP §2163(II)(A)(3)(a) also discusses Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 927, 69 USPQ2d 1886, 1894-95 (Fed. Cir. 2004), where a method of using a PGHS-2 inhibitor did not meet the written description as the inhibitor itself was not sufficiently described, clearly indicating that written description of the compound is still required in a method of using that compound. In this case, it is clear from the specification that the invention is in a new chimeric antigen receptor, or at the least disclosure of a new antibody that could not have been envisaged from the prior art indicates that the prior art was not in possession of all “Lym1 antibodies”. Thus, the prior art cannot provide sufficient written description of this genus of compounds and the specification as filed, disclosing three complete pairs of sequences for the antigen binding fragment, does not sufficiently describe the genus either as there is an unknown amount of structurally distinct antibodies in this genus (see Amgen and Centocor decisions discussed above).
To satisfy the written description requirement, a patent 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. See, e.g., Vas-Cath, Inc., v. Mahurkar, 935 F.2d at 1563, 19 U.S.P.Q.2d at 1116. The claimed invention as a whole may not be adequately described where an invention is described solely in terms of a method of its making coupled with its function and there is no described or art-recognized correlation or relationship between the structure of the invention and its function. An antibody described only by functional characteristic, such as antibody that binds Lym1 or one of the claimed epitopes, without any known or disclosed correlation between that function and the structure of the sequence, is not a sufficient identifying characteristic for written description purposes, even when accompanied by a method of obtaining the biomolecule of interest. In re Bell, 991 F.2d 781, 26 U.S.P.Q.2d 1529 (Fed. Cir. 1993). In re Deuel, 51 F.3d 1552, 34 U.S.P.Q.2d 1210 (Fed. Cir. 1995). In the instant case, the specification provides insufficient direction or guidance concerning the relationship between the structure of the possible antibody to demonstrate possession of the breadth of the genus of Lym1 antibodies encompassed by the instant claims, especially in view of the unpredictability of such an endeavor. The prior art as evidenced by Edwards et al., 2003 (instant PTO-892) teaches there is a substantially huge antibody diversity produced to one single antigen target. Edwards provides evidence that over 1000 antibodies, all different amino acid sequences, were generated towards one single protein antigen target (see abstract). Without a correlation between structure and function, the claims do little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (“definition by function … does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is”).
Without this guidance or direction the skilled artisan would not consider applicant to be in possession of the claimed genus of antibodies because the skilled artisan recognizes that even seemingly minor changes made without guidance or direction as to the relationship between the particular amino acid sequence of the instantly claimed antibody and its ability to bind antigen, can dramatically affect antigen-antibody binding.
Applicant has not described the claimed invention sufficiently to show they had possession of the claimed genus of an antibody that binds Lym1. Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features. See University of Rochester v. G.D. Searle & Co., 358 F.3d 916, 69 USPQ2d 1886 (Fed. Cir. 2004).
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. 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.
What constitutes a "representative number" is an inverse function of the skill and knowledge in the art. Satisfactory disclosure of a "representative number" depends on whether one of skill in the art would recognize that the applicant was in possession of the necessary common attributes or features of the elements possessed by the members of the genus in view of the species disclosed. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only three species within the genus.
To provide adequate written description and evidence of possession of the claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. In the instant case, the only factors present in the claims are a recitation of one generic, broad genus that encompassed a diverse and huge number of possible antibodies that bind the disclosed epitope. The specification does not provide a consistent structure for all of the possible antibodies and fails to provide a representative number of species for the claimed genus. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states 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 they invented what is claimed.” (See Vas-Cath at page 1116).
With the exception of specifically disclosed antibodies with specific sequences, the skilled artisan cannot envision the detailed chemical structure of all of the encompassed antibodies, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The product itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483. In Fiddes, claims directed to mammalian FGF's were found to be unpatentable due to lack of written description for that broad class. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115).
Therefore, claims 33, 39-40, and 42 do not meet the written description requirement.
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 30-45 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5, 7-12, 14-16, and 21-23 of U.S. Patent No. 11,667,715 B2, hereinafter ‘715. Although the claims at issue are not identical, they are not patentably distinct from each other because they recite the same antigen binding fragments and chimeric antigen receptors that are disclosed, as well as the same methods of use.
‘715 recites a humanized Lym1 antibody comprising SEQ ID NOs: 6 and 8, see reference’s claims 1 and 5, which are a 100% match for instant SEQ ID NOs: 6 and 8. ‘715 also recites that the intracellular signaling domain comprises DAP10 and DAP12 intracellular signaling domains as well as a peptide comprising SEQ ID NO: 36, which is a 100% match for instant SEQ ID NO: 36, inserted between the antigen binding domain and the hinge region, see reference’s claims 9 and 10. ‘715 also discloses that the humanized Lym1 antibody can be used in a chimeric antigen receptor (CAR) comprising: (a) an antigen binding domain of the humanized Lym1 antibody, (b) a hinge domain, (c) a transmembrane domain, and (d) an intracellular signaling domain, see reference’s claims 7-10. ‘715 also discloses an isolated nucleic acid sequence comprising the heavy chain immunoglobulin variable sequence or light chain immunoglobulin variable sequence of reference’s claim 1 and operatively linked to a promoter and/or enhancer element, see reference’s claims 11-12. This isolated nucleic acid sequence can be contained in an isolated cell wherein the immune cell is a T-cell or a natural killer cell, see reference’s claims 11-12 and 14-16. ‘715 also discloses a method of habiting the growth of a tumor and/or treating a cancer that expresses Lym1 using the immune cell containing the chimeric antigen receptor of the previous claims, see reference’s claim 21. ‘715 also discloses additional anti-cancer therapeutics such as checkpoint inhibitors, regulatory T cells (Treg), myeloid derived suppressor cells (MDSC), Fluorouracil (5-FU), Histone deacetylase (HDAC) inhibitors, IL-12 treatment, CpG (TLR9 agonists), and/or stimulator of interferon genes (STING) pathway agonists to treat tumor or cancer cells which overexpress Lym1 or expresses CD19, see reference’s claims 22-23.
‘715 reads on instant claims 30-31 wherein the sequences for the antigen binding fragment for humanized Lym1 are a match, instant claim 32 wherein the intracellular signaling domain comprises DAP10 and DAP12 intracellular signaling domains and a peptide is inserted after the antigen binding domains, instant claim 33 where a chimeric antigen receptor comprises (a) an antigen binding domain of the humanized Lym1 antibody, (b) a hinge domain, (c) a transmembrane domain, and (d) an intracellular signaling domain and (e) intracellular signaling domains comprises DAP10 and DAP12, instant claims 34-35 wherein the chimeric antigen receptor comprises SEQ ID NOs: 6 and 8 as a scFv, instant claims 36-37 wherein the hinge domain is a CD8a alpha hinge domain with a leader sequence (see reference’s specification on pg. 34 and claim 11), instant claims 38-42 wherein the anti-Lym1 chimeric antigen receptor is an isolated immune cell that is a T-cell or natural killer cell, instant claim 43 wherein the chimeric antigen receptor is used in a method of inhibiting growth of a tumor and or treating cancer that expresses the Lym1 epitope, instant claim 44 wherein the same further anti-cancer therapeutics are taught, and instant claim 45 wherein the tumor or cancer cell overexpresses Lym1 or expresses CD19.
Conclusion
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/SELAM BERHANE/Examiner, Art Unit 1675
/AURORA M FONTAINHAS/Primary Examiner, Art Unit 1675