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 Status
The remarks filed 10/06/2025 are acknowledged.
Claims 54-73 are pending.
Claims 1-53 are canceled.
Applicant’s election without traverse of Group I, claims 54-65 and 68-73, in the reply filed on 10/06/2025 is acknowledged. Applicant’s election of the following species without traverse in the reply filed on 10/06/2025 is acknowledged: SEQ ID NOs: 30, 36, and 8 for the VH CDRs 1-3, SEQ ID NOs: 9, 10, and 11 for the VL CDRs 1-3, SEQ ID NO: 3 for the VH, SEQ ID NO: 5 for the VL, SEQ ID NOs: 40, 42, 45, and 43 for the VH-FRs 1-4, SEQ ID NOs: 44, 46, 47, and 48 for the VL-FRs 1-4, SEQ ID NO: 15 for the scFv, CD28, SEQ ID NO: 17 for the TM and co-stimulatory domain, FcRy, SEQ ID NO: 18 for the activation domain, and SEQ ID NO; 20 for the full CAR sequence.
Claims 66-67 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 10/06/2025.
Therefore, claims 54-65 and 68-73 are under examination.
Priority
The instant application is a 371 of PCT/IL2020/051215 and claims priority to provisional applications 63/069,051 and 62/940,274. Priority is given with the earliest effective filing date of 11/26/2019.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 07/26/2022, 03/02/2023, 07/17/2023, and 07/01/2024 are in compliance with the provisions of 37 CFR 1.97, except where noted. Accordingly, the information disclosure statement is being considered by the examiner.
The lined through document (i.e. Foreign Patent Document #14) on the 10 page IDS submitted on 07/26/2022 was not considered because it was not attached. Applicant did attach, however, WO 2021105989, which was not cited on the IDS. The lined through documents (i.e. NPL Documents 1 and 11) on the 8 page IDS submitted on 07/26/2022 were not considered because they were not attached.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). See paragraphs 0169-0171 of the instant specification.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Drawings
The drawings are objected to because Figures 1, 2A-2D, 3, 4A-4B, 5A-5B, 6A-6C, 9A-9D, 10A-10E, and 12A-12B have pixelated backgrounds. 37 CFR 1.84(a)(1) which requires that “india ink, or its equivalent that secures solid black lines, must be used for drawings.” 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.
Claim Objections
Claim 57 is objected to because of the following informalities: The claim recites the limitation “(i) at least 2 of said non-conservative substitutions is for proline amino acid residue” which is grammatically awkward and should read as “(i) at least 2 of said non-conservative substitutions is for a proline amino acid residue.” Appropriate correction is required.
Claim 58 is objected to because of the following informalities: The claim recites the limitation “a positively charged amino acid residue selected from Lys or Arg.” The “Lys” and “Arg” should be spelled out and the claim should read as “a positively charged amino acid residue selected from Lysine and Arginine.” Appropriate correction is required.
Claim 59 is objected to because of the following informalities: The claim recites the limitation in option (i) “the VL-FR 1 comprises acid sequences SEQ ID NO: 44;” which should read as “the VL-FR 1 comprises the amino acid sequence of SEQ ID NO: 44.” Claim 59 also recites in option (i) “VH-CDR 1, 2 and 3” and recites in options (ii) and (iii) “VL-FR1”. The Examiner recommends amending the claim to recite “VH-CDRs 1, 2, and 3” in option (i), “VL-FR 1” in option (ii), and “VL-FRs 1” in option (iii) for consistency in the claim language. Appropriate correction is required.
Claim 69 is objected to because of the following informalities: The claim recites the limitation “(i) the cell expresses or capable of expressing the CAR” which is grammatically awkward and should read as “(i) the cell expresses or is capable of expressing the CAR.” Appropriate correction is required.
Claim 71 is objected to because of the following informalities: The claim recites the limitation “…according claim 68…” which should read as “…according to claim 68…”. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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 54-65 and 68-73 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.
Claims 55-65 and 69 depend from claim 53 which has been canceled. Because claim 53 is canceled, the limitations of claim 53 are unknown. Thus, the limitations of claims 55-65 and 69 are also unknown since they are dependent on claim 53. Therefore, claims 55-65 and 69 are indefinite.
For purposes of examination, the Examiner will interpret claims 55-65 and 69 as depending from independent claim 54.
Claims 54-56, 61, 64-65 recite the limitation “having amino acid sequence”, “comprises amino acid sequence”, or “comprising amino acid sequence”. It is unclear if this requires the entire amino acid sequence of the named SEQ ID NO, or if only two consecutive recited amino acids within the sequence of the named SEQ ID NO are required for each of the sequences. Therefore, the scope of these claims is indefinite.
Claims 57-60, 62-63, and 69, which are being interpreted as depending from claim 54, and claims 68 and 70-73 which depend from claim 54, are therefore indefinite for the same reasons.
Note: This 112(b) rejection can be overcome by amending the claims to recite “the amino acid sequence” or “comprises SEQ ID NO: X” with X being the respective sequence number.
Claim 57 recites the limitation of “The CAR according to claim 56, characterized by at least one of: (i) at least 2 of said non-conservative substitutions is for proline amino acid residue.” However, claim 56 recites “(i) the VH-CDR2 comprises at least one non-conservative substitution;…(iv) wherein the antigen binding domain further comprises at least 2 or 3, or 4 non-conservative substitutions of amino acids in the framework sequence of a domain selected from (a) the VH domain.” Therefore, it is unclear if the “at least 2 of said non-conservative substitutions is for proline amino acid residue” as recited in claim 57 is referring to (i), (iv), or both (i) and (iv) in claim 57. Therefore, the scope of this claim is indefinite.
Claim 63 recites the limitation “or an analog thereof having at least 85% amino acid identity to said sequences” in regards to (i) the TM domain, “or an analog thereof having at least 85% amino acid identity to the original sequence and any combination thereof” in regards to (ii) the costimulatory domain. There is insufficient antecedent basis for this limitation in the claim. The lack of antecedent basis arises from claim 63’s dependence on claim 62 where there is no mention of a “sequence” or “sequences” for TM domain or the costimulatory domain. Additionally, without knowing the sequence of reference, it is unclear what a sequence comprising “at least 85% amino acid identity” would be. Therefore, the scope of this claim is also indefinite.
Claim 64 recites the limitation “(i) the TM domain and the costimulatory domain have amino acid sequence SEQ ID NO: 17 or an analog thereof having at least 85% amino acid identity to the sequence.” It is unclear if the TM domain and the costimulatory domain both separately comprise the amino acid sequence of SEQ ID NO: 17 or if the TM domain and the costimulatory domain together comprise the amino acid sequence of SEQ ID NO: 17. Claim 64 also recites the limitation “(iii) the activation domain is FcRy having amino acid sequence SEQ ID NO: 18 or an analog thereof having at least 85% amino acid identity to the original sequence.” It is unclear if “the original sequence” is referring to SEQ ID NO: 18 or to another sequence for FcRy. Therefore, the scope of this claim is indefinite.
Claim 68 recites the limitation “the nucleic acid molecule encoding the same or the construct or vector comprising the nucleic acid molecule”. There is insufficient antecedent basis for this limitation in the claim. The lack of antecedent basis arises from claim 68’s dependence on claim 54 where a “nucleic acid molecule”, “construct”, or “vector” is not mentioned.
Claim 69 recites the limitation “the cell according to claim 56, wherein the cell…”. There is insufficient antecedent basis for this limitation in the claim. The lack of antecedent basis arises from claim 69’s dependence on claim 56 where a “cell” is not mentioned.
Claim 70 recites the limitation of “the nucleic acid encoding the CAR”. There is insufficient antecedent basis for this limitation in the claim. The lack of antecedent basis arises from claim 70’s dependence on claim 54 where a “cell” is not mentioned.
Claim 72 recites the limitation “administering a therapeutically effective amount of cells according to claim 68 or a pharmaceutical composition comprising same.” It is unclear if “comprising same” means the pharmaceutical composition comprises the cells of claim 68 or comprise the same thing as the cells of claim 68 (i.e. the pharmaceutical composition comprises the CAR). Therefore, the scope of this claim is indefinite.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 62 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 62 recites the limitation “wherein the CAR comprises a transmembrane domain (TM domain), a costimulatory domain, and an activation domain. A CAR necessarily comprises these domains, as evidenced by Ahmad et al., 2022, who teaches CARs are made of a ligand binding domain, linker, hinge region, transmembrane domain, and intracellular signaling/activation domain [see Figure 1] and that activation requires a co-stimulatory domain (i.e. signaling domain) [see page 3, section 2.4]. If the CAR of claim 54 does not comprise these components, then this would necessitate a rejection of claim 54 under 35 U.S.C. 112(b) because the meaning of “chimeric antigen receptor (CAR)” would be unclear. Therefore, claim 62, as is being interpreted as depending from claim 54, does not further limit claim 54 because these are inherent components of a CAR. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 112(a)
Written Description
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 54, 56-58, 60-64, and 68-73 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.
Claim 54 is drawn to a chimeric antigen receptor (CAR) comprising an antigen binding domain that binds specifically to Sialyl Lewis A glycan (SLeA), wherein the antigen binding domain comprises three complementarity determining regions (CDRs) and four framework (FR) domains of a heavy-chain variable domain (VH) having amino acid sequence as set forth in SEQ ID NO: 1 and three CDRs and four FRs of a light-chain variable domain (VL) having amino acid sequence as set forth in SEQ ID NO: 4, or an analog thereof having at least 90% sequence identity to said sequences. Further, claim 56, which requires the specific CDRs as set forth in 55, includes the limitation of wherein the VH-CDR2 comprises at least one non-conservative substitution, and claim 60 includes the limitation of (i) the CAR further comprising at least one conservative substitution in the framework(s) of the VH domain and/or VL domain, wherein the resulted VH domain has at least 90% sequence identity to SEQ ID NO: 3 and/or the resulted VL domain has at least 90% sequence identity to SEQ ID NO: 5. Additionally, claim 61 includes the limitation of wherein the scFv (i.e. the VL and VH domains) comprises amino acid sequence selected from SEQ ID NO: 15 and 37 or an analog thereof having at least 90% sequences identity to said sequences.
The specification teaches a CAR comprising an antigen biding domain comprising a VH comprising SEQ ID NO: 3 and a VL comprising SEQ ID NO: 5 [see paragraph 5]. The specification also teaches a CAR comprising a VH comprising an antigen biding domain comprising a VH comprising SEQ ID NO: 1 and a VL comprising SEQ ID NO: 4 or a VH comprising SEQ ID NO: 2 [see paragraph 6]. Further, the specification teaches specific CDR combinations for the VH and VL CDRs 1-3, respectively [see paragraphs 6-7, 33, 44, 58 (Table 1) and 90]. Regarding claim 56, the specification teaches 2 sets of VH-CDR2 that have a single specific non-conservative mutation [see paragraph 47 and Table 1]. The specification further teaches very specific substitutions at explicit positions in the framework regions [see paragraphs 50-53]. However, the specification does not teach a functional antigen binding domain that binds specifically to SLeA that comprises less than 100% sequence identity to SEQ ID NOs: 1, 2, or, 3 for the VH or SEQ ID NOs: 4 or 5 for the VL and/or the CDRs comprised therein (SEQ ID NOs: 2 and 3 comprise specific substitutions relative to SEQ ID NO: 1 and SEQ ID NO: 5 comprises specific substitutions relative to SEQ ID NO: 4).
One means of providing adequate written description and evidence of possession of a claimed genus is through providing 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 this case, the claim does not require that the modifications in the analog be made in a particular region of the sequences, and thus, the claims are drawn to a broad genus of a heavy chain sequence and a light chain sequence of an antigen binding domain with up to 11 single amino acid insertions, substitutions, or deletions in the VH domain (i.e. SEQ ID NO: 1) and up to 10 single amino acid insertions, substitutions, or deletions in the VL domain (i.e. SEQ ID NO: 4). Further, claim 56 does not limit the non-conservative substitution in the VH-CDR2 to a specific residue and allows for more than one substitution, which is not supported by the specification. Claims 60, like claim 54, allows for 10% sequence variation in the VH and VL domains relative to SEQ ID NOs: 3 and 5, respectively, without any requirement for the modifications to be made in a particular region of the sequences. Claim 60 also allows for 10% sequence variation in the scFv (i.e. the VL and VH) relative to SEQ ID NO: 15 of 37 without any requirement for the modifications to be made in a particular region of the sequences.
Claims 54, 56, 60, and 61 are drawn to a variable sequence for the heavy chain of the antigen binding domain and a variable sequence for the light chain of the antigen binding domain without any requirement for where these modifications occur within the sequences. The art recognizes that even a single amino acid change within a CDR region of an antibody can completely abrogate the binding specificity of the antibody (see Kussie et al., 1994 (instant PTO-892)). Further, Rudikoff et al., 1982 (instant PTO-892) teaches that small numbers of substitutions in antibodies may alter antigen-binding specificity [see Abstract]. Thus, making changes to the CDR regions in the heavy chain and light chain sequences 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 functional characteristics of antibodies (including binding specificity) are dictated on their structure. Amino acid sequence and conformation 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. For example, Vajdos et al., 2002 (instant PTO-892) teaches that, “ … Even within the Fv, antigen binding is primarily mediated by the complementarity determining regions (CDRs), six hypervariable loops (three each in the heavy and light chains) which together present a large contiguous surface for potential antigen binding. Aside from the CDRs, the Fv also contains more highly conserved framework segments which connect the CDRs and are mainly involved in supporting the CDR loop conformations, although in some cases, framework residues also contact antigen. As an important step to understanding how a particular antibody functions, it would be very useful to assess the contributions of each CDR side-chain to antigen binding, and in so doing, to produce a functional map of the antigen-binding site." The art shows an unpredictable effect when making single versus multiple changes to any given CDR. For example, Brown et al., 1996 (instant PTO-892) describes how the VHCDR2 of a particular antibody was generally tolerant of single amino acid changes, however the antibody lost binding upon introduction of two amino changes in the same region.
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.)
University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404. 1405 held
that:
...To fulfill the written description requirement, a patent specification must
describe an invention and does so in sufficient detail that one skilled in the art can
clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines Inc. , 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re
Gosteli , 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (" [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the
inventor] invented what is claimed."). Thus, an applicant complies with the written
description requirement "by describing the invention, with all its claimed limitations, not
that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention."
Lockwood, 107 F.3d at 1572, 41 USPQ2d 1966.
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. The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if
the disclosure "indicates that the patentee has invented species sufficient to constitute
the gen[us]. "See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v.
Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir.
2004) "[A] patentee of a biotechnological invention cannot necessarily claim a genus
after only describing a limited number of species because there may be unpredictability
in the results obtained from species other than those specifically enumerated."). "A
patentee will not be deemed to have invented species sufficient to constitute the genus
by virtue of having disclosed a single species when ... the evidence indicates ordinary
artisans could not predict the operability in the invention of any species other than the
one disclosed." In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir.
2004).
Thus, based on the teachings of the instant specification and the art, Applicant
has failed to meet the written description of antigen binding domains that bind specifically to SLeA that comprises less than 100% sequence identity to SEQ ID NOs: 1, 2, or, 3 for the VH or SEQ ID NOs: 4 or 5 for the VL and/or the CDRs comprised therein. Therefore, one of skill in the art would not conclude that Applicant was possession of the instantly claimed invention.
Claims 57-58, 62-64, and 69, which are being interpreted as depending from claim 54, and claims 68, and 70-73 which depend from claim 54, are therefore deficient for the same reasons above and do not meet the written description requirement.
It is noted that claims 55, 59, and 65 require specific sequences for the CDRs and/or the whole CAR which meet the written description requirement.
Claims 63 and 64 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.
Claim 63 is drawn to the CAR, wherein the CAR is characterized by at least one of: (i) the TM domain is a TM domain of a receptor selected from CD28 and CD8, or an analog thereof having at least 85% amino acid identity to said sequences; (ii) the costimulatory domain is selected from a costimulatory domain of a protein selected from CD28, 4-1BB, OX40, iCOS, CD27, CD80, and CD70, an analog thereof having at least 85% amino acid identity to the original sequence and any combination thereof; (iii) the TM domain and the costimulatory domain are both derived from CD28; (iv) wherein the antigen binding domain is linked to the TM domain via a spacer; (v) wherein the activation domain is selected from FcRy and CD3-zeta activation domains; and (vi) further comprising a leading peptide. Claim 64 is drawn to the CAR of claim 63, wherein the CAR is characterized by at least one of: (i) the TM domain and the costimulatory domain have amino acid sequence SEQ ID NO: 17 or an analog thereof having at least 85% amino acid identity to the sequence; (ii) the spacer comprises amino acid sequence comprising from 1 to 4 repetitions of amino acid sequence SEQ ID NO: 16; (iii) the activation domain is FcRy having amino acid sequence SEQ ID NO: 18 or an analog thereof having at least 85% amino acid identity to the original sequence; and (vi) the leading peptide has amino acid sequence SEQ ID NO: 19 or an analog thereof having at least 85% amino acid identity.
The specification teaches SEQ ID NO: 17 for the TM domain and/or the costimulatory domain for CD28 [see paragraphs 73 and 183], SEQ ID NO: 18 for the FcyR ITAM intracellular signaling domain [see paragraph 183], and SEQ ID NO: 19 for the signaling peptide [see paragraphs 82 and 183]. The specification further teaches that “analog” refers to a polypeptide, peptide or protein which differs by one or more amino acid alterations (e.g., substitutions, additions or deletions of amino acid
residues) from the original sequence, having at least 70% sequence identity to the original sequence and still maintains the properties of the parent polypeptide, peptide or protein. The specification provides no examples of “analogs” of SEQ ID NOs: 17, 18, or 19, of analogs for CD28 and CD8 for the TM domain, or of analogs for CD28, 4-1BB, OX40, iCOS, CD27, CD80, and CD70 for the costimulatory domain. The specification further does not provide any guidance on which residues could be modified while still maintaining the function of the recited proteins, nor does the specification teach any functional “analog” of the recited proteins.
One means of providing adequate written description and evidence of
possession of a claimed genus is through providing 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 this case, the claim does not require that the modifications be made at specific amino acid residues or in a particular region of the sequences, and thus, the claims are drawn to a broad genus of “analogs” for the recited proteins.
Claims 63 and 64 are drawn to variable sequences for TM domain, costimulatory domain, the activation domain, and the leading peptide without any requirement for where modifications can occur within the parent sequences. Making deletions, insertions, or substitutions to a polypeptide sequence, while requiring the polypeptide to still maintain its function, is highly unpredictable. Bhattacharya et al., 2017 (instant PTO-892) teaches that the range of possible effects of even single variations at the protein level are significantly greater than currently assumed by existing software prediction methods, and that correct prediction of consequences remains a significant challenge [page 18, third paragraph]. Fenton et al., 2020 (instant PTO-892) teaches that while it is well known that most substitutions at conserved amino acid positions (which they call “toggle” switches) abolish function, it is also true that substitutions at nonconserved positions (which they call “rheostat” positions) are equally capable of affecting protein function, and that each substitution has a different functional outcome, and the set of substitutions spans a range of outcomes [see Abstract]. Further, Guo et al., 2004 (instant PTO-892) teaches that the effects of mutations on protein function are largely additive [page 9207, left column, third paragraph], supporting that when multiple mutations are introduced, there is even less predictability. Thus, it is clear that the structure of variable sequences of proteins does not predictably correlate with the function thereof.
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.)
University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404. 1405 held that:
...To fulfill the written description requirement, a patent specification must
describe an invention and does so in sufficient detail that one skilled in the art can
clearly conclude that "the inventor invented the claimed invention." Lockwood v.
American Airlines Inc. , 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re
Gosteli , 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (" [T]he
description must clearly allow persons of ordinary skill in the art to recognize that [the
inventor] invented what is claimed."). Thus, an applicant complies with the written
description requirement "by describing the invention, with all its claimed limitations, not
that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention."
Lockwood, 107 F.3d at 1572, 41 USPQ2d 1966.
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. The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if
the disclosure "indicates that the patentee has invented species sufficient to constitute
the gen[us]. "See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v.
Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir.
2004) "[A] patentee of a biotechnological invention cannot necessarily claim a genus
after only describing a limited number of species because there may be unpredictability
in the results obtained from species other than those specifically enumerated."). "A
patentee will not be deemed to have invented species sufficient to constitute the genus
by virtue of having disclosed a single species when ... the evidence indicates ordinary
artisans could not predict the operability in the invention of any species other than the
one disclosed." In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir.
2004).
Thus, based on the lack of teachings in the specification and the teachings in the art, Applicant has failed to meet the written description of “analogs” of SEQ ID NOs: 17, 18, or 19, of analogs for CD28 and CD8 for the TM domain, or of analogs for CD28, 4-1BB, OX40, iCOS, CD27, CD80, and CD70 for the costimulatory domain. Therefore, one of skill in the art would not conclude that Applicant was in possession of the instantly claimed invention.
Claim Rejections - 35 USC § 112(a)
Enablement
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 72 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating lung adenocarcinoma, pancreatic adenocarcinoma, colon adenocarcinoma, HER-2 negative breast carcinoma, and pharynx squamous cell carcinoma, does not reasonably provide enablement for treating all types of cancer encompassed by the instant claims. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
As a general rule, enablement must be commensurate with the scope of claim language. MPEP 2164.08 states, “The Federal Circuit has repeatedly held that “the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation’.” In re Wright, 999 F.2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)” (emphasis added). The “make and use the full scope of the invention without undue experimentation” language was repeated in 2005 in Warner-Lambert Co. v. Teva Pharmaceuticals USA Inc., 75 USPQ2d 1865, and
Scripps Research Institute v. Nemerson, 78 USPQ2d 1019 asserts: “A lack of enablement for the full scope of a claim, however, is a legitimate rejection.” The principle was explicitly affirmed most recently in Auto. Tech. Int’l, Inc. v. BMW of N. Am., Inc., 501 F.3d 1274, 84 USPQ2d 1108 (Fed. Cir. 2007), Monsanto Co. v. Syngenta Seeds, Inc., 503 F.3d 1352, 84 U.S.P.Q.2d 1705 (Fed. Cir. 2007), and Sitrick v.
Dreamworks, LLC, 516 F.3d 993, 85 USPQ2d 1826 (Fed. Cir. 2008). See also In re Cortright, 49 USPQ2d 1464, 1466 and Bristol-Myers Squibb Co. v. Rhone-Poulenc Rorer Inc., 49 USPQ2d 1370.
The factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have been described in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988). Among these factors are: (1) the nature or the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary. When the above factors are weighed, it is the examiner’s position that one skilled in the art could not practice the invention without undue experimentation. Some experimentation is not fatal; the issue is whether the amount of experimentation is “undue”; see In re Vaeck, 20 USPQ2d 1438, 1444.
(1) The nature of the invention and (5) The breadth of the claims:
The claim is drawn to a method for treating cancer in a subject in need thereof comprising administering a therapeutically effective amount of cells according to claim 68 (which comprise the CAR of claim 54) or a pharmaceutical composition comprising the same. Claim 73 adds the limitation of wherein the cancer is selected from lung adenocarcinoma, pancreatic adenocarcinoma, colon adenocarcinoma, Her-2 negative breast carcinoma and pharynx squamous cell carcinoma.
The claims are broad and inclusive of all types of cancer or neoplasia in humans generally. The breadth of the claim exacerbates the complex nature of the subject matter to which the present claims are directed. The claims are extremely broad
due to the vast number of possible cancer types and tumor cell growth mechanisms represented by the phrase “treating or delaying progression of cancer.” Cancer is not a single disease, or cluster of closely related disorders. There are hundreds of cancers, which have in common only some loss of controlled cell growth. Cancers are highly heterogeneous at both the molecular and clinical level, something seen especially in, for example, the cancers of the breast, brain and salivary glands. They can occur in pretty
much every part of the body.
(2) The state of the prior art and (4) The predictability or unpredictability of the art:
While the state of the art is relatively high with regard to the treatment of specific cancer types, the state of the art with regard to treating cancer broadly is underdeveloped. In particular, there is no known anticancer treatment that is effective against all cancer cell types. The cancer treatment art involves a very high level of unpredictability. While the state of the art is relatively high with regard to the treatment of specific cancers with specific agents, it has long been underdeveloped with regard to the treatment of cancers broadly. The lack of significant guidance from the present specification or prior art with regard to the actual treatment of all cancers with the claimed method, requiring that the claimed method results in a synergistic reduction in tumor volume, makes practicing the claimed invention unpredictable.
With regard to cancer treatment, Bally et al. (US 5,595,756) stated, “Despite enormous investments of financial and human resources, no cure exists for a variety of diseases. For example, cancer remains one of the major causes of death. A number of bioactive agents have been found, to varying degrees, to be effective against tumor cells. However, the clinical use of such antitumor agents has been highly compromised because of treatment-limiting toxicities” [column 1, lines 17-24]. Sporn et al., 2000 (instant PTO-892) teaches the magnitude of mortality of cancers and that mortalities are in fact still rising and that new approaches to a variety of different cancer are critically needed. Sporn also teaches that “given the genotype and phenotype heterogeneity of advanced malignant lesions as they occur in individual patients, one wonders just exactly what are the specific molecular and cellular targets for the putative
cure.”
Furthermore, the art indicates the difficulties in going from in vitro to in vivo for drug development for treatment of cancers. Auerbach et al., 2000 (instant PTO-892) indicates that “one of the major problems in angiogenesis research has been the difficulty of finding suitable methods for assessing the angiogenic response. For example, the 96 well rapid screening assay for cytokinesis was developed in order to
permit screening of hybridoma supernatants…In vitro tests in general have been limited by the availability of suitable sources for endothelial cells, while in vivo assays have proven difficult to quantitate, limited in feasibility, and the test sites are not typical of the in vivo reality” [page 167, left column, 1st paragraph]. Further, as taught by HogenEsch et al., 2012 (instant PTO-892), there is no single cell culture or in vivo cancer model that faithfully predicts the efficacy of anticancer drugs in human clinical trials. Cell culture approaches offer the advantage of human-derived cell lines or tissue fragments from primary tumors, but cannot mimic the complexity of the reciprocal interaction between the growing tumor and the co-evolving microenvironment. Xenografts in immunodeficient mice have limited added value over cell culture models as the lack of an intact immune system and insufficient interactions between the human tumor cells and mouse stromal cells do not recapitulate human cancers. Thus, the art recognizes that going from in vitro studies to in vivo studies for cancer drug developments are difficult to achieve.
Given Bally’s teaching of treatment-limiting toxicities in clinical use, Sporn’s teaching that the cancer progression is heterogeneous as it progresses, both in genotype and phenotype, Auerbach’s teaching that one of the major problems in angiogenesis research has been the difficulty of finding suitable methods for assessing the angiogenic response, and HogenEsch’s teaching that there is no single cell culture or in vivo cancer model that faithfully predicts the efficacy of anticancer drugs in human clinical trial, these teachings collectively demonstrate that the treatment of cancer is highly unpredictable, if even possible for many cancers.
(6) the amount of direction or guidance presented; (7) the presence or absence of working examples:
There is a lack of working examples in the specification for treating all types of cancer encompassed by the instant claims. Applicant has provided evidence of treating colorectal and pancreatic cancer [see Example 3], pharynx squamous cell cancinoma [see Examples 5 and 6], and teaches that lung adenocarcinoma, pancreatic adenocarcinoma, colon adenocarcinoma, and HER-2 negative breast cancer cells express SLeA, suggesting these may be targeted and treating using the CAR [see Example 7]. However, Applicant has not provided any substantive evidence of treating any type of cancer with the CAR. Because the cancers encompassed by the instant claims are so disparate and no single cancer example can be representative of all the other encompassed cancers, a demonstration of treatment or support of a given condition does not provide support for the breadth of the claims.
In conclusion, the claimed invention does not provide enablement for treating all types of cancer encompassed by the instant claims. Thus for the reasons outlined above, the specification is not considered to be enabling for one skilled in the art to make and use the claimed invention as the amount of experimentation required is undue, due to the broad scope of the claims, the lack of guidance and working examples provided in the specification. Therefore, the specification is not representative of the instant claims and the specification is not fully enabled for the instant claims. In view of the above, one of skill in the art would be forced into undue experimentation to practice the claimed invention.
The Examiner recommends amending claim 72 to recite “A method for treating an SLeA expressing cancer…” to overcome this rejection.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 54-63 and 68-73 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 30-37 and 45 of copending Application No. 17/779,720 (‘720; reference application) in view of Chmielewski et al., 2013 (instant PTO-892).
Regarding claim 54, 57-58, and 60 of the instant application, claim 30 of ‘720 teaches a monoclonal antibody (mAb) or a fragment thereof that specifically binds to Sialyl Lewis A glycan (SLeA), wherein the mAb or the fragment comprises an antigen binding domain comprising a heavy-chain variable domain (VH) and a light-chain variable domain (VL) each comprising three complementarity determining regions (CDRs) wherein the VH-CDR 1, 2 and 3 comprise amino acid sequences SEQ ID NOs: 15, 12, and 8, respectively, and the VL-CDRs 1, 2 and 3 comprise amino acid sequences SEQ ID NOs: 9, 10 and 11, claim 34 of ‘720 teaches the mAb or the fragment according claim 30, wherein the VH domain comprises amino acid sequence set forth in SEQ ID NO: 3 and the VL domain comprises amino acid sequence set forth in SEQ ID NO: 5, claim 35 of ‘720 teaches the mAb or the fragment according to claim 30, wherein the fragment is a single chain variable fragment (scFv), and claim 36 of ‘720 teaches the mAb or the fragment according to claim 35, wherein the scFv comprises an1ino acid sequences SEQ ID NO: 3 and SEQ ID NO: 5.
SEQ ID NO: 3 of ‘720 has 95.9% sequence identity to SEQ ID NO: 1 of the instant claim and SEQ ID NO: 5 of ‘720 has 98.9% sequence identity to SEQ ID NO: 4 of the instant claim. Regarding claim 60, SEQ ID NOs: 3 and 5 of ‘720 have 100% sequence identity to SEQ ID NOs: 3 and 5, respectively, of the instant claim. Additionally, regarding claims 57 and 58, SEQ ID NO: 3 has non-conservative substitutions at positions 1, 110, 114 relative to SEQ ID NO: 1.
However, ‘720 does not specifically teach a chimeric antigen receptor (CAR) comprising the mAb (i.e. antigen binding domain).
Chmielewski teaches that antibody-based CAR T cells enables the targeting of antigens of different compositions and structure such as peptides, carbohydrates, or inorganic compounds [page 2, left column, second paragraph] and further teaches CARs comprising antibodies that target T cells toward carbohydrate antigens like CA19-9 (i.e. SLeA) [page 2, right column, third paragraph].
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the CAR that targets CA19-9 (SLeA) of Chmielewski to comprise the mAb (antigen-binding domain) of ‘720 that binds SLeA. One would have been motivated to make this modification because It is prima facie obvious to substitute equivalents known for the same purpose (see MPEP 2144.06 (II)). Further, one would have been motivated to use these sequences for the antigen binding domain that binds to SLeA because they are known sequences, and it is obvious to use known variations for predictable outcomes. See MPEP 2143 (F).
Regarding claims 55, 56, and 59, claim 31 of ‘710 teaches the mAb or fragment according to claim 30, wherein VHCDR1 comprises amino acid sequence selected from SEQ ID NO: 6 and 15, and the VH-CDR2 comprises amino acid sequence selected from SEQ ID NO: 12 and 21 and claim 32 of ‘720 teaches the mAb or fragment according to claim 30, wherein the CDRs 1, 2, and 3 of the VH domain comprises an1ino acid sequences SEQ ID NOs: 15, 21 and 8, respectively, the CDRs 1, 2, and 3 of the VL domain comprise amino acid sequences SEQ ID NOs: 9, 10 and 11, respectively, a VH-framework domains (FRs) 1, 2, and 4 amino acid sequences SEQ ID NOs: 24, 26 and 27, respectively, and a VL-FR1 comprising the amino acid sequence SEQ ID NO: 28, and claim 33 of ‘720 teaches the mAb or fragment according to claim 30, comprising: i. a set of six CDR sequences comprising SEQ ID NOs: 15, 21, 8, 9, 10 and 11; ii. a set of four VH framework sequences comprising SEQ ID NOs: 24, 26, 29 and 27; and iii. a set of four VL framework sequences comprising SEQ ID NOs: 28, 30, 31 and 32.
SEQ ID NOs: 15, 21, and 8 of ‘720 have 100% sequence identity to SEQ ID NOs: 15, 21, and 8 of the instant claims, respectively, and SEQ ID NOs: 9, 10, and 11 of ‘720 have 100% sequence identity to SEQ ID NOs: 9, 10, and 11 of the instant claims, respectively.
Regarding claim 61, claim 37 of ‘720 teaches the mAb or fragment according to claim 36, wherein the scFv comprises amino acid sequence SEQ ID NO: 22 or an analog thereof having at least 90% sequence identity to said sequence.
SEQ ID NO: 22 of ‘720 has 100% sequence identity to SEQ ID NO: 15 of the instant claim.
Regarding claim 62, these are inherent properties of a CAR, and are therefore necessarily present in the CAR as taught by Chmielewski.
Regarding claim 63, Chmielewski teaches that the CD3 gamma chain initiates the downstream signaling for T-cell activation (i.e. activation domain) [see page 2, Figure 1].
Regarding claim 68-70, Chmielewski teaches CAR modified T cells [page 1, right column, third paragraph and page 3, right column, see “The CAR Strategy” section].
Regarding claim 71, claim 45 of ‘720 teaches a pharmaceutical composition comprising the mAb or the fragment according to claim 30 or a conjugate thereof, and a pharmaceutically acceptable carrier.
Regarding claims 72 and 73, ‘720 teaches a method of treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the antibodies [0029] and also teaches the method comprises administering a pharmaceutical composition comprising cells or expressing the mAb to the subject [0119]. ‘720 further teaches that the cancer is lung or pancreatic adenocarcinomas, colon carcinoma, HER2-neg breast carcinoma, or pharynx squamous cell carcinoma [0028 and 0113]. See the decisions in Sun Pharmaceuticals v Eli Lily Fed Cir July 28, 2010; Geneva v GlaxoSmithKline 349, F.3d 1373; and Pfizer v Teva 518 F3d 1353 supporting the Office's use of disclosed utilities of compositions when applying double patenting rejections to method claims.
This is a provisional nonstatutory double patenting rejection.
Claims 54-64 and 68-73 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 30-37 and 45 of copending Application No. 17/779,720 (‘720; reference application) in view of Chmielewski et al., 2013 (instant PTO-892), as applied to claims 54-63 and 68-73 above, and further in view of Perera (WO2018057585; instant PTO-892).
The teachings of ‘720 and Chmielewski are above.
However, ‘720 and Chmielewski do not specifically teach that the leading peptide has the amino acid sequence of SEQ ID NO: 19, as set forth in option (vi) of instant claim 64.
Regarding claim 64, Perera teaches the use of a signal (leading) peptide (i.e. N-terminal to the antigen binding domain) in the structure of a CAR which facilitates expression of the CAR on the surface of the cell and can be the mouse immunoglobulin light chain kappa signal sequence consisting of SEQ ID NO: 4 [page 32, lines 27-33 – page 33, lines 1-3].
SEQ ID NO: 4 of Perera has 100% sequence identity to SEQ ID NO: 19 of the instant claim.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the CAR, as taught by ‘720 and Chmielewski, to comprise the signal peptide of Perera. One would have been motivated to have made this modification because Perera teaches that the signal peptide facilitates expression of the CAR on the cell surface, and further, one would have been motivated to have used the sequence of Perera for the signal peptide sequence because it is a known sequence in the art, and it is obvious to use known variations in the prior art for predictable outcomes. See MPEP 2143 (F).
Claims 54-65 and 68-73 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 30-37 and 45 of copending Application No. 17/779,720 (‘720; reference application) in view of Chmielewski et al., 2013 (instant PTO-892) and Perera (WO2018057585; instant PTO-892), as applied to claims 54-64 and 68-73 above, and further in view of Zhang (WO 2018200586; instant PTO-892), Bublik (WO 2019030757; instant PTO-892), and Chen et al., 2013 (instant PTO-892).
The teachings of ‘720, Chmielewski, and Perera are above.
However, ‘720, Chmielewski, and Perera do not specifically teach that the CAR comprises the amino acid sequence of SEQ ID NO: 20.
Regarding claim 65, SEQ ID NO: 20 of instant claim 65 comprises multiple sequences for different components as shown below:
- Residues 1-22 of SEQ ID NO: 20 correspond to SEQ ID NO: 19 for the leading peptide.
- Residues 23-259 of SEQ ID NO: 20 correspond to SEQ ID NO: 15 for the scFv.
- Residues 260-269 correspond to 2 repeats of SEQ ID NO: 16 for the spacer.
- Residues 270-379 correspond to SEQ ID NO: 17 for the TM domain and the costimulatory domain.
- Residues 380-417 correspond to SEQ ID NO: 18 for the FcRy activation domain.
To reiterate the teachings, Perera teaches the use of a signal (leading) peptide of SEQ ID NO: 4 which has 100% sequence identity to SEQ ID NO: 19 of the instant claim. ‘720 teaches the scFv of SEQ ID NO: 22 which has 100% sequence identity to SEQ ID NO: 15.
Zhang teaches a CD28 transmembrane/intracellular signaling domain fusion protein that can be used in the construction of a CAR comprising SEQ ID NO: 530 [see paragraph 0418].
SEQ ID NO: 530 of Zhang has 100% sequence identity to SEQ ID NO: 17 of the instant application.
Bublik teaches SEQ ID NO: 10, a human Fc gamma receptor, for the activation domain of a CAR [0011]. Bublik further teaches a CAR comprising a leader peptide, an antigen binding domain, a TM domain of CD28, a costimulatory domain of CD28, and an activation domain of FcRy [0011]. Bublik also teaches that there is a spacer between the antigen binding domain and the transmembrane domain [0045].
SEQ ID NO: 10 of Bublik has 100% sequence identity to SEQ ID NO: 18 of the instant application.
Chen teaches a linker of GGGGS(2) which is a flexible linker (spacer) for the use in fusion proteins (i.e. a CAR) that improves biological activity [see page 1360, Table 3].
The individual sequences when put together create a sequence with 100% sequence identity to SEQ ID NO: 20 of the instant claim.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have combined the individual sequences, as taught by the respective art, to arrive at SEQ ID NO: 20 of the instant claim. One would have been motivated to combine these specific components to arrive at the claimed CAR because they are known components in the art for creating a functional CAR. Further, one would have been motivated to use these sequences for each of the components that form SEQ ID NO: 20 because they are known sequences in the art, and it is obvious to use variations known in the art for predictable outcomes. See MPEP 2143 (F).
Claims 54 and 68-72 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 47, 56-57, and 60-63 of copending Application No. 18/261,149 (‘149; reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
Regarding claim 54 of the instant application, claim 47 of ‘149 teaches an isolated monoclonal antibody (mAb) or a fragment thereof that specifically binds to Sialyl Lewis A glycan (SLeA), wherein the mAb or the fragment comprises an antigen binding domain comprising a heavy-chain variable domain (VH) and a light-chain variable domain (VL) each comprising three complementarity determining regions (CDRs) and four framework domains (FR), wherein the VH-CDR 1 and 2 comprise the amino acid sequences SEQ ID NOs: 3 and 4, respectively, VH-CDR 3 comprises an amino acid sequence selected from SEQ ID NO: 5 and 9; VL-CDRs 1 and 3 comprise the amino acid sequences SEQ ID NOs: 6 and 12, respectively; and VL-CDR 2 comprises an amino acid sequence selected from SEQ ID NO: 10 and SEQ ID NO: 11, claim 56 of ‘149 teaches a chimeric antigen receptor (CAR) comprising the mAb (i.e. antigen binding domain) or the fragment thereof according to claim 47 or the humanized from thereof, and claim 57 of ‘149 teaches The CAR according to claim 56, wherein the CAR comprises (i) a VH and VL comprising amino acid sequences SEQ ID NO: 17 and 18, respectively; (ii) a VH and VL comprising amino acid sequences SEQ ID NO: 19 and 20, respectively; (iii) a VH and VL comprising amino acid sequences SEQ ID NO: 23 and 24, respectively; (iv) a VH and VL comprising amino acid sequences SEQ ID NO: 25 and 24, respectively; (v) a single chain variable fragment (scFv) comprising an amino acid sequence selected from SEQ ID NO: 21 and 22; or (vi) a humanized scFv comprising an amino acid sequence selected from SEQ ID NO: 26 and 27.
SEQ ID NO: 17 of ‘149 has 97.7% sequence identity and SEQ ID NO: 19 of ‘149 has 98.4% sequence identity to SEQ ID NO: 1 of the instant claim for the VH. SEQ ID NO: 18 of ‘149 has 95.2% sequence identity and SEQ ID NO: 20 of ‘149 has 94.8% sequence identity to SEQ ID NO: 4 of the instant claim for the VL. Thus, options (i) and (ii) of claim 57 meet the limitation of “an analog thereof having at least 90% sequence identity to said sequences” as set forth in instant claim 54.
Regarding claim 68 of the instant application, claim 60 of ‘149 teaches a cell comprising at least one of: (i) the mAb or the fragment thereof according to claim 47,
(ii) a humanized form of the mAb or the fragment thereof according to claim 47, (iii)
a CAR comprising the mAb or the fragment of (i) or (ii), (iv) the nucleic acid molecule encoding at least one chain of the mAb or the fragment of (i) or (ii) or the CAR of (iii),
(v) a nucleic acid construct comprising the nucleic acid molecule of (iv), and (vi) a vector comprising the nucleic acid molecule of (iv) or the nucleic acid construct of (v).
Regarding claims 69 and 70 of the instant application, claim 61 of ‘149 teaches the cell according to claim 60, wherein the cell (i) is selected from a T cell and a natural killer (NK) cell, (ii) expresses or is capable of expressing the CAR, or (iii) both (i) and (ii).
Regarding claim 71 of the instant application, claim 62 of ‘149 teaches a composition comprising the isolated monoclonal antibodies or fragments thereof of claim 47, or conjugates or a CAR comprising same, or a plurality of cells comprising thereof and a carrier, optionally wherein the composition is a pharmaceutical composition and the carrier is a pharmaceutically acceptable carrier.
Regarding claim 72 of the instant application, claim 63 of ‘149 teaches a method for treating cancer in a subject in need thereof comprising administering to said subject a therapeutically effective amount of isolated monoclonal antibodies or fragments thereof according claim 47, or the conjugates thereof, or CAR comprising same or cells comprising same.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims are allowed.
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/B.E.D./Examiner, Art Unit 1675
/JEFFREY STUCKER/Supervisory Patent Examiner, Art Unit 1675