The Examiner of your application in the USPTO has changed. To aid in correlating any papers for this application, all further correspondence regarding this application should be directed to Supervisory Examiner Julie Wu.
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 .
Claims 1, 2, 6, 9-11, 15, 18-22, 24, 25, 28-30, 32, 33, 34, and 36 are pending.
In the reply of May 23, 2025, Applicant's election without traverse of Group I and a species comprising: laminins as the modified protein/protein in the extracellular space, an scFv as the antigen binding domain, CD28 as the costimulatory domain, and acetylation as the modified process.
Claims 19-22, 24, 25, 28-30, and 32-33 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on May 23, 2025.
Claims 1, 2, 6, 9-11, 15, 18, 34, and 36 are being examined on the merit.
Rejections Withdrawn
All previous rejections of claims 3, 12,and 14 are moot in view of claim cancellation.
Previous claims 1, 2, 6, 9-11, 15, 18, 34, and 36 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35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement are withdrawn after reconsideration.
Previous rejection of claims 1-2, 9-11, 15,18, 34 and 36 under 35 U.S.C. 103 as being unpatentable over Guillonneau et al (WO2017042170A1) and further in view of Eshhar (WO2008095141A2) and Korpos ( Current Pharmaceutical Design, 2009, 15, 1349-1357) is withdrawn in view of claim amendments.
New Rejections
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 1, 2, 6, 9-11, 15, 18, 34, and 36 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.
Base claims 1 and 10 recite “optionally” prior to “derived from a CD3 chain domain” is exemplary language and renders the claim indefinite, because it is unclear whether the limitations following the phrase “optionally” are part of the claimed invention. See MPEP 2173.05(d).
Further if the terms “derived from a CD3 chain domain” are required for the claims, it is unclear which domain(s) of the CAR is optionally derived from a CD3 chain domain.
Claims 2, 6, 9-11, 15, 18, 34, and 36 includes the limitation of claim 1 and are also indefinite. Thus, the metes and bounds are unclear.
New Rejections Necessitated by Claim Amendments
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.
Claims 1-9, 12-14, and 16 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a written description rejection.
Scope of the claimed genus
The claims are directed to chimeric antigen receptor (CAR) comprising an antigen binding domain that specifically binds to an antigen comprising an acetylated laminin, wherein the antigen binding domain is an antibody, antibody fragment, single chain variable fragment (scFv) or an aptamer. The instant specification defined “specifically binds”:
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Thus, the claims encompasses a genus of an antibody, antibody fragment, single chain variable fragment (scFv) or an aptamer that selectively binds to an epitope on laminin that is acetylated.
Description of representative species in the specification
The specification discloses CAR comprising an antigen binding domain that specifically binds to a large list of basement membrane proteins including laminin (0097, 0102, and 0105). There are 5 recitation of laminin amongst a large list of basement membrane proteins (0097, 0102, and 0105). On paragraph 0105 of the instant specification, there is disclosure that the antigen binding domain of the CAR can bind to acetylated basement membrane proteins, including laminin.
The instant specification does not teach specific acetylation of laminin and does not teach any antibodies or aptamer that specifically bind to acetylated laminin.
State of the relevant art
Acetylation
Acetylation is a major post-translational modification where an acetyl group is added to the N-terminus of proteins or the [Symbol font/0x65]-amino group of lysine residues (Drazic, Biochimica et Biophysica Aceta, 2016, 1864:1372-1401; specifically abstract, page 1372, left column). Acetylation is mediated by a family of Nt-acetylatransferases (NATs) (page 13472, right column). NATs have specific substrate specificities (page 1375, see “2.2.2. NATs vary in their substrate specifcities”).
Acetylation of Laminin
Laminin is a heterotrimeric glycoproteins composed of [Symbol font/0x61], [Symbol font/0x62], and [Symbol font/0x67] chains that is integral for the integrity of the basement membrane (Champliaud et al., Experimental Cell Research, 2000, 259:326-335; page 326, right column, 1st paragraph). Champliaud teaches that laminin is glycosylated (abstract). Champliaud also teaches conventional monoclonal and polyclonal antibodies that binds to laminin [Symbol font/0x67]1, [Symbol font/0x62]1, or [Symbol font/0x62]2 chain (page 327, left column, see “Antibodies”). Champliaud is silent if the laminin proteins are acetylated.
Charonis (The Journal of Cell Biology, 1988, 107:1253-1260) investigated the regions of laminin that interacts with heparin. Charonis teaches an F-9 peptide comprising “RYVVLPRPVCFEKGMNYTVR”, which corresponds to residues 641-660 of the [Symbol font/0x62]1 chain of laminin that can be acetylated in vitro (page 1254, left column, see “Modification of Peptide F-9”’; Table I). Charonis teaches that F-9 peptide binds directly to heparin, and can compete with full length laminin from binding to heparin (figures 2 and 3). Interestingly, in vitro acetylation of the F-9 peptide abrogated its ability to bind to heparin (abstract; figure 3). However, at the time of filing, studies have not confirmed that laminin is acetylated on the lysine of “RYVVLPRPVCFEKGMNYTVR”.
The next publication regarding acetylation of laminin did not occur until Gao (Frontiers in Medicine, 2023, 9:1030644, pages 1-19) after the filing of the instant application. Gao performed multi-omics analysis of acetylated proteins, acetylomics, in mice with cigarette smoke-induced chronic obstructive pulmonary disease (COPD), a chronic inflammatory disease (abstract). Gao teaches that acetylomics of COPD mice showed that laminin is acetylated (figure 4G). Gao did not characterize the acetylation of laminin and the functional significance of the acetylation.
Specific NATs that can acetylate laminin has not been described in the arts.
It is unclear which residues of laminin is acetylated in vivo, especially during inflammation. Further, neither antibodies nor aptamers that will “specifically bind” to acetylated laminin are not taught in the arts. Further, the instant specification does not disclose any antibodies or aptamers that will “specifically bind” to acetylated laminin.
Antibody binding epitopes
It was well-known in the antibody art at the time of filing, the formation of an intact antigen-binding site in an antibody typically requires the association of the complete heavy and light chain variable regions of a given antibody, each of which comprises three CDRs (or hypervariable regions) which provide the majority of the contact residues for the binding of the antibody to its target epitope (Sela-Culang et al., Frontiers in immunology, 2013, 4:302, pages 1-13).
Sela-Culang further teaches that antigens lack intrinsic properties that clearly differentiate between epitopic and non-epitopic residues, and any part of the antigen surface my become part of an epitope under some circumstances (page 2, see “Ab Epitope Prediction”).
In the same vein, Edwards (Journal of molecular biology, 2003, 334: 103-118) endeavored to uncover the breadth of the structural diversity of antibodies a single antigen can give rise to. Edwards employed a phage display library to screen for antibodies that bind a single protein, BLyS, and isolated over 1000 unique anti-BLyS antibodies, each comprising a different amino acid sequence (Abstract). These antibodies were structurally diverse, resulted from nearly all possible Vh, D, and Jh, germlines (Pg. 105; “Vh and Vl germline usage”), and comprised 568 distinct Vh CDR3 sequences, ranging in length from 5 to 25 amino acid residues (Fig. 4; “Vh CDR3 sequence diversity”; Pg. 105). Together, these works highlight that neither knowledge of the antigen sequence nor the antibody sequence is necessarily predictive of its function.
Even if the specific residues of acetylated laminin is known, based on the state of the art, a skilled artisan cannot predict the structure of a genus of antibodies that will specifically bind to acetylated laminin as required by the instant claims. No amount of epitope mapping is disclosed, and there is no functional relationship established between the claimed antigens, antigen sequences, or particular subsequences of the instant claims and the structure of an antibody capable of binding these targets.
Identifying characteristics and structure/function correlation
The written description requirement for a claimed genus may be satisfied 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 a CAR comprising an antigen binding domain that binds to acetylated laminin. To meet this requirement in the instant case, the specification must describe structural features that the skilled artisan as of the effective filing date would have expected to convey the CAR comprising an antibody or aptamer that can specifically bind to acetylated laminin. However, not even one specific species of an antibody or aptamer that specifically binds to acetylated laminin have been described in the arts or disclosed in the instant specification.
Because the art has not characterized acetylation of laminin, particularly in inflammation, and there is no teachings or disclosure of an antibody or aptamer that specifically binds to acetylated laminin, the Applicant is not in possession of a CAR comprising an antigen binding domain that specifically binds to acetylated laminin.
Claims 1, 2, 6, 9-11, 15, 18, 34, and 36 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention. This is an enablement rejection.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is "undue." These factors include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988) (MPEP 2164.01(a)).
The claims are directed to chimeric antigen receptor (CAR) comprising an antigen binding domain that specifically binds to an antigen comprising an acetylated laminin, wherein the antigen binding domain is an antibody, antibody fragment, single chain variable fragment (scFv) or an aptamer. The instant specification teaches “specifically binds” means:
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Thus, the claims encompasses a genus of an antibody, antibody fragment, single chain variable fragment (scFv) or an aptamer that selectively binds to an epitope on laminin that is acetylated.
State of the prior art
Acetylation
Acetylation is a major post-translational modification where an acetyl group is added to the N-terminus of proteins or the [Symbol font/0x65]-amino group of lysine residues (Drazic, Biochimica et Biophysica Aceta, 2016, 1864:1372-1401; specifically abstract, page 1372, left column). Acetylation is mediated by a family of Nt-acetylatransferases (NATs) (page 13472, right column). NATs have specific substrate specificities (page 1375, see “2.2.2. NATs vary in their substrate specifcities”).
Acetylation of Laminin
Laminin is a heterotrimeric glycoproteins composed of [Symbol font/0x61], [Symbol font/0x62], and [Symbol font/0x67] chains that is integral for the integrity of the basement membrane (Champliaud et al., Experimental Cell Research, 2000, 259:326-335; page 326, right column, 1st paragraph). Champliaud teaches that laminin is glycosylated (abstract). Champliaud also teaches conventional monoclonal and polyclonal antibodies that binds to laminin [Symbol font/0x67]1, [Symbol font/0x62]1, or [Symbol font/0x62]2 chain (page 327, left column, see “Antibodies”). Champliaud is silent if the laminin proteins are acetylated.
Charonis (The Journal of Cell Biology, 1988, 107:1253-1260) investigated the regions of laminin that interacts with heparin. Charonis teaches an F-9 peptide comprising “RYVVLPRPVCFEKGMNYTVR”, which corresponds to residues 641-660 of the [Symbol font/0x62]1 chain of laminin that can be acetylated in vitro (page 1254, left column, see “Modification of Peptide F-9”’; Table I). Charonis teaches that F-9 peptide binds directly to heparin, and can compete with full length laminin from binding to heparin (figures 2 and 3). Interestingly, in vitro acetylation of the F-9 peptide abrogated its ability to bind to heparin (abstract; figure 3). However, at the time of filing, studies have not confirmed that laminin is acetylated on the lysine of “RYVVLPRPVCFEKGMNYTVR”.
The next publication regarding acetylation of laminin did not occur until Gao (Frontiers in Medicine, 2023, 9:1030644, pages 1-19) after the filing of the instant application. Gao performed multi-omics analysis of acetylated proteins, acetylomics, in mice with cigarette smoke-induced chronic obstructive pulmonary disease (COPD), a chronic inflammatory disease (abstract). Gao teaches that acetylomics of COPD mice showed that laminin is acetylated (figure 4G). Gao did not characterize the acetylation of laminin and the functional significance of the acetylation.
Specific NATs that can acetylate laminin has not been described in the arts.
Because it is unclear which residues of laminin is acetylated, and antibodies or aptamers that will “specifically bind” to acetylated laminin are not taught in the arts. Further, the instant specification does not disclose any antibodies or aptamers that will “specifically bind” to acetylated laminin.
Antibody binding epitopes
It was well-known in the antibody art at the time of filing, the formation of an intact antigen-binding site in an antibody typically requires the association of the complete heavy and light chain variable regions of a given antibody, each of which comprises three CDRs (or hypervariable regions) which provide the majority of the contact residues for the binding of the antibody to its target epitope (Sela-Culang et al., Frontiers in immunology, 2013, 4:302, pages 1-13).
Sela-Culang further teaches that antigens lack intrinsic properties that clearly differentiate between epitopic and non-epitopic residues, and any part of the antigen surface my become part of an epitope under some circumstances (page 2, see “Ab Epitope Prediction”).
In the same vein, Edwards (Journal of molecular biology, 2003, 334: 103-118) endeavored to uncover the breadth of the structural diversity of antibodies a single antigen can give rise to. Edwards employed a phage display library to screen for antibodies that bind a single protein, BLyS, and isolated over 1000 unique anti-BLyS antibodies, each comprising a different amino acid sequence (Abstract). These antibodies were structurally diverse, resulted from nearly all possible Vh, D, and Jh, germlines (Pg. 105; “Vh and Vl germline usage”), and comprised 568 distinct Vh CDR3 sequences, ranging in length from 5 to 25 amino acid residues (Fig. 4; “Vh CDR3 sequence diversity”; Pg. 105). Together, these works highlight that neither knowledge of the antigen sequence nor the antibody sequence is necessarily predictive of its function.
Even if the specific residues of acetylated laminin is known, based on the state of the art, a skilled artisan cannot predict the structure of a genus of antibodies that will specifically bind to acetylated laminin as required by the instant claims. An unreasonable amount of experimentation is required to identify a genus of antibody to bind to a specific epitope.
The amount of direction provided by the inventor & the existence of working examples:
The specification discloses CAR comprising an antigen binding domain that specifically binds to a large list of basement membrane proteins including laminin (0097, 0102, and 0105). There are 5 recitation of laminin amongst a large list of basement membrane proteins (0097, 0102, and 0105). On paragraph 0105 of the instant specification, there is disclosure that the antigen binding domain of the CAR can bind to acetylated basement membrane proteins, including laminin. The instant specification does not teach any antibodies or aptamer that specifically binds to acetylated laminin.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Based on the state of art and the instant disclosure, it is unclear which lysine(s) is acetylated on laminin. An unreasonable amount of experimentation would be required to identify the specific lysine(s) that is acetylated on laminin, particular during inflammation.
Further, also based on the state of art and the instant disclosure, even if the acetylated region of laminin is known, there is an unreasonable amount of experimentation is required to isolate antibodies or aptamer that will specifically bind to acetylated laminin as required by the claims.
Conclusion
No claims allowed.
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/JULIE WU/ Supervisory Patent Examiner, Art Unit 1643
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