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
Election/Restrictions
Applicant’s election without traverse of group I with species CD8αTM, CD3ζ, CD137 (4-1BB), SEQ ID NO:12, CD20, lentiviral vector, and solid cancer in the reply filed on 3/16/2026 is acknowledged.
Claims 1-37 are pending.
Claims 29-37 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claims 1-28, drawn to chimeric antigen receptor comprising polypeptide comprising an extracellular binding domain comprising CDRH1-3, transmembrane domain, and Intracellular signaling domain, are examined on merits.
Information Disclosure Statement
The information disclosure statement (s) (IDS) submitted on 9/22/2022 are/is considered by the examiner and initialed copies/copy of the PTO-1449 are/is enclosed.
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.
1. Claims 6-7 are rejected as lack of antecedent basis for recitation “the VL domain” of claim 1.
Claim 6 recites “The chimeric antigen receptor according to claim 1, …..wherein the VL comprises….( line 4).
Claim 7 recited “….the chimeric antigen receptor of claim 1…..wherein the VL comprises an amino acid sequence of SEQ ID NO: 80.”
There is insufficient antecedent basis for such limitation set forth in claim 1. Claim 1 does not contain any recitation of a VL domain.
The lack of clarity could arise where a claim refers to “said lever” or “the lever,” where the claim contains no earlier recitation or limitation of a lever and where it would be unclear as to what element the limitation was making reference. Similarly, if two different levers are recited earlier in the claim, the recitation of “said lever” in the same or subsequent claim would be unclear where it is uncertain which of the two levers was intended (See MPEP 2173.05).
2. Claim 7 is rejected because it recites VL comprises an amino acid sequence of SEQ ID NO: 7 or 8, which does not clearly define the sequence SEQ ID NO: 7 or 8. The Phrase “an amino acid sequence of SEQ ID NO: 7 or 8” reads as few as two amino acids in the sequence. Amending the claims recite the amino acid sequence of SEQ ID NO: 7 …or 8 would obviate the rejection.
3. Claims 1-28 are rejected because of unclear recitation of the claims, e. g. claim 14 recites
….. a CDRH2 sequence of SEQ ID NO: 2; ……
such recitations are not clearly defined how long and what amino acids of CDRH2 is from SEQ ID NO: 2 because a CDR of an antibody contains 3-20 amino acids in length and the instant SEQ ID NO: 2 has 17 amino acids in length. The recitation “a CDRH2 sequence of SEQ ID NO: 2” could read the CDR having as small as two amino acids in length. Amending the claims as
……a CDRH2 comprising (or consisting of) the sequence of SEQ ID NO: 2…… would overcome the rejection.
The base claims 1, 14 and 28 etc. could render the dependent claims indefinite.
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.
Scope of Enablement:
Claims 1, 5-13, and 15-27 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 a Chimeric Antigen Receptor (CAR) comprising an extracellular domain (antibody) to Clausdin-3 comprising a full set of six CDRs comprising CDRH1-3 sequences of SEQ ID NOs: 1, 2 and 3 respectively paired to CDRL1-3 sequences of SES ID NOs: 4, 5 and 6 or both heavy chain variable region (VH) having the sequence of SEQ ID NO: 7 paired to the light chain variable region (VL) having the sequence of SEQ ID NO: 8, does not reasonably provide enablement for any antigen fragments of an antibody, which do not contain a full set of 6 CDRs or contain only VH or VL domain. 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 or use the invention commensurate in scope with these claims. This is enablement rejection.
Factors to be considered in determining whether a disclosure meets the enablement requirement of 35 USC 1 12, first paragraph, have been described by the court in In re Wands, 8 USPQ2d 1400 (CA FC 1988).
Wands states on page 1404,
“Factors to be considered in determining whether a disclosure would require undue experimentation have been summarized by the board in Ex parte Forman. They include (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims.''
The claims are drawn to
A chimeric antigen receptor comprising a polypeptide comprising:
a) an extracellular domain which comprises a claudin-3 binding domain comprising a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 1 (CDRH1) sequence of SEQ ID NO: 1; a heavy chain complementarity determining region 2 (CDRH2) sequence of SEQ ID NO: 2; a heavy chain complementarity determining region 3 (CDRH3) sequence of SEQ ID NO: 3;
b) a transmembrane domain; and c) one or more intracellular signaling domains,
wherein the VH comprises an amino acid sequence of SEQ ID NO: 7 (VH),
wherein the extracellular domain comprises an amino acid sequence having at least 90% or 95% sequence identity to SEQ ID NO: 11 (scFv), or an amino acid sequence having one, two, three, four, or five amino acid substitutions, insertions, or deletions relative to SEQ ID NO: 11 or 18 (scFv) (claim 8). …..
engineered immune effector cell comprising CAR of claim 1 (claim 17)
pharmaceutical composition comprising engineered immune effector cell (claim 24)
Polynucleotide encoding the CAR of claim 1 (claim 21).
Method of treating cancer in patient comprising administering to patient the pharmaceutical composition of claim 24.
Applicant is noted:
1 claim 1 does not contain a set of CDRL1-3 from light chain or VL, which is recited in claim 2 (not included in this rejection) and claim 6 (SEQ ID NO: 8 as VL).
Claim 6 is included in the rejection because it recites alternative VH or VL.
2. both SEQ ID NOs: 11 and 18 recited in claims 8 are scFv that contain CDRH1-3 described in claim 1 and CDRL1-3 of claim 2 (see ScvUi). Thus, reciting up to 90% sequence identity to SEQ ID NO: 11 or 18 (scFv) or amino acid substitutions would include the amino acid alternations in the sequences of CDRL1-3 from VL domain of SEQ ID NO: 8, therefore, claim 8 is included in this rejection.
Thus, the claimed encompass a CAR comprising extracellular domain, an antibody fragments that do not contain a full set of 6 CDRs (1) and amino acid alternations in CDRL1-3 with up to 10% sequences identity (2).
The specification teaches chimeric antigen receptor (CAR) comprising extracellular domain binding to Claudin 3 expressed on cancer cell for cancer treatment (abstract and figure 1) and teaches one example antibody having CDRH1-3 having the sequences of SEQ ID NOs: 1-3 paired to CDRL1-3 having the sequences of SEQ ID NOS: 4-6 and then contemplates that the CDRs may be modified by at least one amino acid substitutions, deletions or additions and the variants retain the antigen binding and biological characteristics as the unmodified antibody ([0117-1279] and [0179]+ of Pg publication). The specification although lists a few conservative amino acid substitutions (table 2), there is no reduced practice of any of amino acid substitutions within the CDRs and to test the activities and functions. The specification also defines extracellular antigen binding domain in the CAR usually derives from a monoclonal antibody comprising scFv, Fab, etc. [0102].
Regarding with base claim 1 and dependent claims reciting extracellular domain of CAR containing CDRH1-3 only (missing CDRL1-3) and specification does not disclose any CAR having an extracellular domain containing only CDRH1-3 or VH domain or less than full set of 6 CDRs that could perform the function of Claudin-3 binding and treating a cancer expressing Claudin-3 (example 4+).
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”). 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, 1993). Even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function as evidenced by Rudikoff et al (Proc. Natl. Acad. Sci. USA 1982 Vol. 79: page 1979). Rudikoff et al teach that the alteration of a single amino acid in the CDR of a phosphocholine-binding myeloma protein resulted in the loss of antigen-binding function. The fact that not just one CDR is essential for antigen binding or maintaining the conformation of the antigen binding site, is underscored by Casset et al (BBRC 307, 198-205 2003), 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 CDRH3 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.). Pascalis et al (The Journal of Immunology vol 169, 3076-3084, 2002) 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.).
It is unlikely that the antibody and antigen binding fragment thereof as defined by the claims, which contain less than the full set of the six CDRs from the heavy and light chain variable regions have the required binding function. Applicants have provided insufficient evidence or nexus that would lead the skilled artisan to predict the ability of using an antibody or an antigen binding fragment containing fewer than 6 CDRs, resulting in the antibody that retains the antigen specificity of the parental non-human antibody. One of skill in the art would neither expect nor predict the appropriate functioning of the antibody as being claimed.
Therefore, in view of the state of the art, no quantity of experimentation and objective evidence, lack of guidance/direction in the specification to predict the function of the antibodies having less than a full set of 6 CDRs to bind to Claudin-3 as extracellular domain in the claimed CAR, one skilled in the art would not make and use the claimed product for the therapeutic purposes, an undue quantity of experimentation would be required to for one skilled in the art to practice the invention as claimed.
Drawn to Written Description:
Claims 1-28 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.
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. Possession may be shown. For claimed product the specification must provide sufficient distinguishing identifying characteristics of the genus, including disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, level of skill and knowledge in the art, and predictability in the art or any combination thereof.
The claims are drawn to
A chimeric antigen receptor comprising a polypeptide comprising:
a) an extracellular domain which comprises a claudin-3 binding domain comprising a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 1 (CDRH1) sequence of SEQ ID NO: 1; a heavy chain complementarity determining region 2 (CDRH2) sequence of SEQ ID NO: 2; a heavy chain complementarity determining region 3 (CDRH3) sequence of SEQ ID NO: 3;
b) a transmembrane domain; and c) one or more intracellular signaling domains,
wherein the VH comprises an amino acid sequence of SEQ ID NO: 7 (VH),
wherein the extracellular domain comprises an amino acid sequence having at least 90% or 95% sequence identity to SEQ ID NO: 11 (scFv), or an amino acid sequence having one, two, three, four, or five amino acid substitutions, insertions, or deletions relative to SEQ ID NO: 11 or 18 (scFv) (claim 8). …
engineered immune effector cell comprising CAR of claim 1 (claim 17)
pharmaceutical composition comprising engineered immune effector cell (claim 24)
Polynucleotide encoding the CAR of claim 1 (claim 21).
Method of treating cancer in patient comprising administering to patient the pharmaceutical composition of claim 24.
Applicant is noted:
1. both SEQ ID NOs: 11 and 18 recited in claims 8 are scFv that contain CDRH1-3 recited in claim 1 and CDRL1-3 set forth in claim 2 (see ScvUi for details). Thus, reciting up to 90% sequence identity to SEQ ID NO: 11 or 18 (scFv) or amino acid substitutions would include the amino acid alternations in the sequences of CDRL1-3 from VL domain of SEQ ID NO: 8.
2. many claims including claims 2-4, 14 and 18 recite e.g. “…a CDRH2 sequence of SEQ ID NO: 2,….“, For the recitation, one skill in the art could read the sequence being a fragment or having as few as two amino acids from the sequence of SEQ ID NO: 2.
Thus, the claims encompass chimeric antibody receptor (CAR) comprising
1) an extracellular domain that is an antibody fragment thereof containing less than a full set of 6 CDRs,
2) amino acid alternations in CDRL1-3 from VL domain with up to 10% sequences identity, and
3) a CDRs contains only a fragment or as few as few amino acids of the recited sequence.
The specification teaches chimeric antigen receptor (CAR) comprising extracellular domain binding to Claudin 3 expressed on cancer cell for cancer treatment (abstract and figure 1) and teaches one example antibody having CDRH1-3 having the sequences of SEQ ID NOs: 1-3 paired to CDRL1-3 having the sequences of SEQ ID NOS: 4-6 and then the CDRs may be modified by at least one amino acid substitution, deletion or addition and the variants retain the protein binding and biological characteristic of the unmodified protein ([0117-1279] and [0179]+, pG publication). The specification although lists a few conservative amino acid substitutions (table 2), there is no reduced practice of the amino acid substitutions within the CDRs and to test the activities and functions. The specification also defines extracellular antigen binding domain in the CAR usually derives from a monoclonal antibody comprising scFv, Fab etc. [0102].
Regarding base claim 1 and dependent claims reciting extracellular domain of CAR containing CDRH1-3 only (missing CDRL1-3), the specification does not disclose that any CAR having extracellular domain without a full set of 6 CDRs could perform the function of Claudin-3 binding and treating a cancer expressing Claudin-3 (example 4).
A description of a genus may be achieved by means of a recitation of a representative number of species falling within the scope of the genus or by describing structural features common the genus that “constitute a substantial portion of the genus.” See University of California v. Eli Lilly and Co., 119 F.3d 1559, 1568, 43 USPQ2d 1398, 1406 (Fed. Cir. 1997): “A description of a genus of cDNAs may be achieved by means of a recitation of a representative number of cDNA, defined by nucleotide sequence, falling within the scope of the genus or of a recitation of structural features common to the members of the genus, which features constitute a substantial portion of the genus.” The Federal Circuit has recently clarified that a DNA molecule can be adequately described without disclosing its complete structure. See Enzo Biochem, Inc. V. Gen-Probe Inc., 296 F.3d 1316, 63 USPQ2d 1609 (Fed. Cir. 2002). The Enzo court adopted the standard that the written description requirement can be met by “show[ing] that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristic, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. “Id. At 1324, 63 USPQ2d at 1613”.
The court has since clarified that this standard applies to compounds other than cDNAs. See University of Rochester v. G.D. Searle & Co., Inc., F.3d ,2004 WL 260813, at *9 (Fed.Cir.Feb. 13, 2004). The instant specification fails to provide that an antibody as an extracellular domain containing VH domain only could perform a function of antigen binding as the whole antibody having a full set of 6 CDRs, and provides insufficient descriptive information in the broadly claimed variants having up to 10% amino acid substitutions in the CDRs of SEQ ID NO: 7 and/or 8. The specification does not provide a specific or detail structural characteristics of the homologous/variants up to 10% amino acid substitutions in the sequence of SEQ ID NO: 11 or 18 (scFv) without definition of CDRs. Thus, one of skill in the art would reasonably conclude that the inventor(s), at the time the application was filed, did not have possession of the claimed invention.
MPEP § 2163.02 states, “[a]n objective standard for determining compliance with the written description requirement is, 'does the description clearly allow persons of ordinary skill in the art to recognize that he or she invented what is claimed' ”. The courts have decided:
The purpose of the “written description” requirement is broader than to merely explain how to “make and use”; the 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.
As stated in the Written Description Guideline (2008), the levels of the skill and knowledge in the art would not be able to identify without further testing which of these variants or portions of the antibody without VL domain could perform the same function as an whole antibody or antigen binding fragment thereof comprising VH paired to VL having the sequences of SEQ ID NOs: 7 and 8. Based on the lack of knowledge and predictability in the art those of ordinary skill in the art would not conclude that the applicant was in possession of the claimed genus of variants having the functions listed in the claims based on the teaching on CDRH1-3 in VH domain of SEQ ID NO: 7 only.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states “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). As discussed above, the skilled artisan cannot envision the detailed chemical structure(s) and functional attribute(s) of the encompassed genus of variants or portion as claimed, 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 compound 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. The specification provided only the bovine sequence.
Therefore, only the claimed CAR comprising an extracellular domain comprising CDRH1-3 comprising/consisting of the sequences of SEQ ID NOs: 1, 2, and 3 from the VH sequence of SEQ ID NO: 7 paired to CDRL1-3 comprising/consisting of the sequences of SEQ ID NOs: 4, 5 and 6 from the VL sequence of SEQ ID NO: 8, but not the full breadth of the claims, meets the written description provision of 35 U.S.C. §112, first paragraph. 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).
Applicant may also refer to Written Description Guideline at USPTO website:
http://www.uspto.gov/web/patents/guides.htm
Example 9 and 10 in particular.
Conclusion
No claims are allowed.
Extracellular domain in the claimed CAR comprising CDRH1-3 having the sequences of SEQ ID NOs: 1, 2 and 3 paired to CDRL1-3 having the sequences of SEQ ID NOs: 4, 5, and 6 are free of prior art.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
US20200038443 discloses a Chimeric Antigen Receptor (CAR) comprising an extracellular domain that is scFv, a transmembrane domain (TM), costimulatory molecule (ICOS, 4-1BB), and one intracellular signal domain (CD3zeta, figures 1-2) as recited in claims. However, the reference does not teach or suggest the scFv is antibody or antigen binding domain to Claudin-3 having the CDR sequences as set forth in the claims.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Lei Yao, whose telephone number is (571) 272-3112. The examiner can normally be reached on 8:00am-6:00pm Monday-Friday.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Samira Jean-Louis, can be reached on (571) 270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/LEI YAO/Primary Examiner, Art Unit 1642
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