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
1. The Amendment filed July 16, 2025 in response to the Office Action of February 25, 2025 is acknowledged and has been entered. Claims 3 and 4 have been cancelled. Claims 1, 2, 6, 8, 11, and 15 have been amended. New claim 17 has been added.
2. Claims 1, 2, and 5-17 are currently being examined.
Drawings
3. The drawings are objected to because Figure 15 A-L is blank in the drawings filed by the Applicant on April 01, 2021, which is different from the drawings filed in international stage application. It is unclear which drawing set should be used if the application should be patented.
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.
Rejections Maintained
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.
4. Claim 9 is 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.
Claim 9 recites the limitation "the nucleic acid molecule " in line 3. There is insufficient antecedent basis for this limitation in the claim because the antecedent portion of the claim recites nucleotide sequences.
Response to Arguments
Applicant argues that regarding claim 9 is amended as shown in the enclosed claim amendments. The rejections may be properly reconsidered and withdrawn.
Applicant's arguments with respect to claim 9 have been considered, but have not been found persuasive. Claim 9 has not been amended, thus the rejections are maintained for the reasons of record.
Rejections Maintained
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.
5. Claims 1, 2, and 5-17 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.
The claims are broadly drawn to a group two molecules wherein the affinity of each individual antigen binding moiety of a CAR molecule of the group to its target antigen is between 50 mM and 100 nM. The antigen binding moieties are not limited to a specific target or a specific structure. Thus, the claims encompass a very large genus of CAR molecules wherein the wherein the affinity of each individual antigen binding moiety of a CAR molecule of the group to its target antigen.
The state of the art is such that it is well known in the art that protein biochemistry is unpredictable and, thus, predicting protein function from structure is unpredictable. The unpredictable sensitivity of proteins interaction and function to alterations of even a single amino acid in a sequence are exemplified Rudikoff et al. (PNAS USA, 1982, 79: 1979-1983) who specifically teach that even minor changes in the amino acid sequence of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function. In particular, Rudikoff et al. teach that alteration of a single amino acid in the CDR of a phosphocholine-binding myeloma protein results in the loss of antigen-binding function. The sensitivity of protein binding interactions to alterations of even a single amino acid in a sequence are exemplified by Coleman et al. (Research in Immunology, 1994; 145(1): 33-36) who teach single amino acid changes in an antigen can effectively abolish antibody antigen binding. Further, the sensitivity of binding proteins to alterations of even a single amino acid in a sequence are exemplified by Burgess et al. (J of Cell Bio. 111:2129-2138, 1990) who teach that replacement of a single lysine reside at position 118 of acidic fibroblast growth factor by glutamic acid led to the substantial loss of heparin binding, receptor binding and biological activity of the protein. Furthermore Pero et al. (US PG Pub 2003/0105000) specifically teach that the SH2 domain of Grb14 is 81% similar to the SH2 domain of Grb7 on the amino acid level, but although Grb7 binds to ErbB2, Grb14 does not bind to ErbB2. Further, although the SH2 domain of Grb2 is only 50% similar to Grb7 on the amino acid level, both Grb2 and Grb7 bind to the same site on ErbB2. See ¶ 0255 of the published application. These references demonstrate that even a single amino acid alteration or what appears to be an inconsequential chemical modification will often dramatically affect the biological activity and characteristics of a binding protein. Additionally, Ibragimova and Wade (Biophysical Journal, Oct 1999, Vol. 77, pp. 2191-2198) teach that factors affecting protein folding and stability are governed by many small and often opposing effects and that even when the “rules” are known for altering the stability of a protein fold by the introduction of a single point mutation the result is not reliable because the balance of forces governing folding differs for different protein sequences, and that the determination of the relative magnitude of the forces governing the folding and stability of a given protein sequence is not straightforward (page 2191, first column, lines 12-17 and second column, lines 3-8). Thus, given the above, it is clear that in the protein biochemistry arts an adequate written description is essential for one of skill in the art to make and use the claimed invention.
Although drawn to DNA arts, the findings in University of California v. Eli Lilly and Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997) and Enzo Biochem, Inc. V. Gen-Probe Inc. are relevant to the instant claims. The Federal Circuit addressed the application of the written description requirement to DNA-related inventions in University of California v. Eli Lilly and Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997). The court stated that "[a] written description of an invention involving a chemical genus, like a description of a chemical species, requires a precise definition, such as by structure, formula, [or] chemical name,' of the claimed subject matter sufficient to distinguish it from other materials." Id. At 1567, 43 USPQ2d at 1405. The court also stated that
a generic statement such as "vertebrate insulin cDNA" or "mammalian insulin cDNA" without more, is not an adequate written description of the genus because it does not distinguish the genus from others, except by function. It does not specifically define any of the genes that fall within its definition. It does not define any structural features commonly possessed by members of the genus that distinguish them from others. One skilled in the art therefore cannot, as one can do with a fully described genus, visualize or recognize the identity of the members of the genus. A definition by function, as we have previously indicated, does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is.
Id. At 1568, 43 USPQ2d at 1406. The court concluded that "naming a type of material generally known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material." Id.
Finally, the court addressed the manner by which a genus of cDNAs might be described. "A description of a genus of cDNAs may be achieved by means of a recitation of a representative number of cDNAs, 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." Id.
The Federal Circuit 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 characteristics ... 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 (emphasis omitted, bracketed material in original).
The inventions at issue in Lilly and Enzo were DNA constructs per se, the holdings of those cases are also applicable to claims such as those at issue here. A disclosure that does not adequately describe a product itself logically cannot adequately describe a method of using that product.
Thus, the instant specification may provide an adequate written description of a group of two CAR molecules wherein the affinity of each individual antigen binding moiety of a CAR molecule of the group to its target antigen is between 50 mM and 100 nM, per Lilly by structurally describing a representative number of said CAR molecules, or by describing "structural features common to the members of the genus, which features constitute a substantial portion of the genus." Alternatively, per Enzo, the specification can show that the claimed invention is complete "by disclosure of sufficiently detailed, relevant identifying characteristics, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics."
In this case, the specification does not provide an adequate written description of a group of two CAR molecules wherein the affinity of each individual antigen binding moiety of a CAR molecule of the group to its target antigen is between 50 mM and 100 nM, in a manner that satisfies either the Lilly or Enzo standards.. Although the specification discloses rcSso7d-based antigen binding moieties mutants (Fig. 2) a EGFR CAR (E11.4.1-G32A)(Figs. 5 and 7), or HER2 affibody (Fig. 10) with low binding affinities or binding affinities in the claimed range, this does not provide a description of a group two molecules wherein the affinity of each individual antigen binding moiety of a CAR molecule of the group to its target antigen is between 50 mM and 100 nM that would satisfy the standard set out in Enzo.
The specification also fails to describe of a group of two CAR molecules wherein the affinity of each individual antigen binding moiety of a CAR molecule of the group to its target antigen is between 50 mM and 100 nM by the test set out in Lilly. The specification describes only a few species of binding molecules with low binding affinities or binding affinities in the claimed range/ Therefore, it necessarily fails to describe a "representative number" of species of peptides. In addition, the specification also does not describe "structural features common to the members of the genus, which features constitute a substantial portion of the genus."
Thus, the specification does not provide an adequate written description of a group of two CAR molecules wherein the affinity of each individual antigen binding moiety of a CAR molecule of the group to its target antigen is between 50 mM and 100 nM that is required to practice the claimed invention or reasonably convey to one skilled in the relevant art that the inventor(s), at the time the application was filed, had possession of the broadly claimed invention.
Response to Arguments
6. Applicant argues that it is well settled in law that section 112(a) requires Applicant to describe in the specification the invention, however, “information which is well known in the art need not be described in detail in the specification.” MPEP §2163(II)(A)(2) and Hybritech, Inc. v. Monoclonal Antibodies, Inc., 802 F.2d 1367, 1379-80, 231 USPQ 81, 90 (Fed. Cir. 1986).
“It is well established in our law that conception of a chemical compound requires that the Inventor be able to define it so as to distinguish it from other materials, and to describe how to obtain it.” Amgen, Inc. v. Chugai Pharm.Co., Ltd., 927 F.2d 1200, 1206, 18 USPQ2d 1016, 1021 (Fed. Cir. 1991)
Applicant argues that In the present case, claim 1 and its dependent claims are directed to a group of chimeric antigen receptors (CARs) consisting of two CAR molecules, wherein the affinity of each individual antigen binding moiety of a CAR molecule of the group to its target antigen is between 50 mM and 100 nM.
Applicant argues that we submit herewith the declaration of Dr. Lehner and ask the USPTO consider the declaration and exhibits.
Applicant argues that the specification provides over 100 pages of description and several practical examples teaching a person of skill in detail how to lower the affinity of an antigen binding moiety, including page 5, embodiments 5 and 6 and claims 3 and 4 of the present application as originally filed (as WO 2020/070290 Al). The present invention uses antigen binding moieties with unusually low affinities compared to CAR concepts disclosed in the prior art (s. our response to the Restriction Requirement mailed October 15, 2024, p. 15, including the Salzer et al. article (Nat. Comm. 11 (2020), 4166; attached as Exhibit B; full version with supplemental figures attached), e.g. at Figs. 1, 2e, 3f,g, 4b,c, 6d; Suppl. Figs. 6A (generation of low-affinity HER2-affibody mutants with alanine-scan) and 12 (data with two nanobodies as binder scaffold); p.3, col. 1, 2"4 para to col. 2, 2" para; p. 5 and 6 and p. 11). These low affinity binders may either be chosen from known low affinity binders or specifically designed by routine experimentation. It was surprising that the on-switch function of the group of CARs enabled by the present invention, i.e. the capability of the group of CARs to activate cells only in presence of a dimerizing regulating molecule, is only possible with such low-affinity binders and is not possible with binders of higher affinity which are the usual and preferred binders used in the present field of technology (reviewed by Hanssens et al. (attached); Kd typically 10-7 - 10 -10 M (i.e. from 100 nM to 100 pM); see Hanssens et al., section 4.1 1 and 2nd paragraph, which summarize and cite the knowledge and work known at the time the present invention was made) and in antibody design in general. The specification provides numerous examples of such low- affinity antigen binding moieties already known in the art. Following the detailed description of the specification a person of skill knows the sequence of each of the moiety (already in the art) and also how it is distinguished from other materials (e.g. an existing binder which already has the low affinity as defined in claim 1 (such as the MSLN-specific binder based on Fibronectin (FN3) scaffold, and the GFP- and HER2-specific nanobody scaffold; s. page 12, lines 1, 3 and 4 and in embodiment 3 of the present application as originally filed (WO 2020/070290 A1)) or a binder which has been mutagenized for lowering its affinity, such as the EGFR- and HER2-specific binders based on the rcSso7d and affibody scaffold used in the examples of the present application) and wherein the affinity of each individual antigen binding moiety of a CAR molecule of the group to its target antigen is lowered to between 50 mM and 100 nM.
Applicant argues that we respectfully submit that Applicant was in possession of the full group consisting of two CAR molecules, as claimed, at the priority date of the above-captioned patent application. The rejection must be reconsidered and withdrawn.
Applicant argues that it appears that the Office Action is arguing that the claims should be restricted to only those molecules which are described in Examples. We respectfully disagree for at least the following reasons. First, there is no requirement in law for such a restriction wherein as here, a person of skill could use any other antigen binding moiety with an affinity of between 50 mM and 100 nM in the same way as provided in examples.
Applicant argues that second, the Lilly and Enzo decisions cited in the Office Action support the fining of full possession of the scope even further because both decisions emphasize that 1) information which is well known in the art need not be described in detail in the specification; and 2) the written description requirement is satisfied when claimed invention is complete “by disclosure of sufficiently detailed, relevant identifying characteristics, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics.”
Applicant argues that functional generic language in the present field of CAR technology is well available and fully known to the person skilled in the art, as i.e. also proven by a high number of granted US patents referring to general architecture of CAR molecules defined by functional and generic claim language which obviously have also fulfilled the written description standards, such as (as three representative examples of a high number of granted US patents with similar claims) US 11,976,116 B2 (an example for a CAR platform with an OR-gate function with no limitation concerning specific antigen binding domains or other specific features), US 12,161,672 B2 (an ON-switchable CAR concept, again without any antigen limitation) and US 12,275,802 B2 (a NOT-gate CAR system with no limitation concerning the tumor antigen).
Applicant argues that the present specification provides over 80 pages and a sequence listing showing exemplary sequences. The specification provides detailed protocols of how a person of skill may e.g. select already known low affinity antigen binding moieties or obtain these moieties of the claimed CARs by mutagenizing original (high affinity) antigen binding moieties in order to lower their binding affinities, as recited in claims and as described in the specification.
Applicant argues that following MPEP §2163(II)(A)(3), a person of skill was fully informed that Applicant was in possession of the claimed invention as a whole at the time the application was filed. We respectfully request that the lack of written description rejection be reconsidered and withdrawn.
7. Applicant’s arguments and the Declaration of Lehner Manfred under 37 CFR 1.132 filed July 16, 2025 are insufficient to overcome the rejection of claims 1, 2, and 5-17 based upon 35 U.S.C. 112(a), as failing to comply with the written description requirement as set forth in the last Office action.
Although the specification and art disclose a few antibodies or binding domains that have binding affinities in the claimed range the current claims are not so limited. Even for one target of a claimed antigen binding moiety, the genus of binding moieties as claimed, which are not limited in structure, is very large and inclusive of structurally distinct molecules like antibodies, non-antibody binding domains, small molecules and nucleic acids. The claims are not limited to even the targets with known or disclosed binding moieties that have binding affinities in the claimed range. Rather the claims encompass a vast genus of molecules to be targeted as partially exemplified by claim 6. As argued by Applicant, the usual antigen binding moieties used in the present field of technology typically have binding affinities of 10-7 - 10 -10 M Kd (i.e. from 100 nM to 100 pM) and are usually antibody scFv domains, see Hanssens et al., section 2 and Fig. 3. Thus, the broad genus of binding moieties that have binding affinities in the claimed range of between 50 mM and 100 nM are not routinely known or used in the art.
Although the specification teaches alanine scanning to identify binding moieties that have binding affinities in the claimed range, screening assays are not sufficient to provide an adequate written description. Although Applicant might argue that one of ordinary skill could screen for the species that would function as claimed, in particular, screening assays do not describe the claimed invention because the court found in that screening assays are not sufficient to describe an invention because they are merely a wish or plan for obtaining the claimed chemical invention. See Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 927, 69 USPQ2d 1886, 1894-95 (Fed. Cir. 2004) and MPEP 2163 IIA(3)(a).
Although other US patents refer to the general architecture of CAR molecules defined by functional and generic claim language, each case is decided on its own merits. Additionally, the cited patents do not specifically claim antigen binding moieties that have binding affinities in the claimed range. A subgenus is not necessarily described by a genus encompassing it and a species upon which it reads. See MPEP 2163.05 (II). Thus, the cited patents do not provide support for description of the claimed antigen binding moiety having a binding affinity of between 50 mM and 100 nM.
In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence for an adequate written description fails to outweigh the evidence of lack of an adequate written description. Thus the rejection is maintained for the reasons previously set forth and above.
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.
8. Claims 1, 2, and 5-17 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 5, 7-11, 16, 17 and 19-21 of co-pending Application No. 17/281,522 (published as US 2022/0041687, IDS) in view of US 2017/0158749 A1 (Cooper et al. June 8, 2017), “Cooper”.
The ‘522 claims are drawn to
1. A group of chimeric antigen receptors (CARs) consisting of two CAR molecules, a first CAR molecule and a second CAR molecule, wherein each member of the group of CARs is different in its amino acid sequence from one another;
wherein each of the CAR molecules of the group comprise at least a transmembrane domain and an ectodomain, and wherein both CAR molecule of the group comprise an endodomain, which comprises at least a signaling region which can transduce a signal via at least one | immunoreceptor tyrosine-based activation motif (ITAM) from human CD3 zeta; wherein the endodomain of each CAR molecule of the group, , is located on the intracellular side of a cell membrane, if expressed in a cell, wherein the ectodomain of each CAR molecule of the group translocates to the extracellular side of a cell membrane, if expressed in a cell, and wherein the transmembrane domain of each CAR molecule of the group is located in a cell membrane, if expressed in a cell; wherein the ectodomain of each CAR molecule of the group in its prevalent conformation is free of cysteine amino acid moieties which are able to form intermolecular disulphide bonds with other CAR molecules of the group, respectively; wherein the antigen binding moieties of the first and second CAR molecules of the group and of the other polypeptides are specific for different target antigens which are not linked to each other covalently;
wherein the affinity of each individual antigen binding moiety of a CAR molecule of the group to its respective target antigen is between 50 mM and 100 nM, and
wherein each CAR molecule of the group comprises heterodimerization domain integrated in the endodomain, which mediates defined heterodimerization with the other CAR molecule
2. The group of CARs according to claim 1, wherein the affinity of each individual antigen binding moiety of a CAR molecule of the group to its target antigen is between 50 mM and 150 nM.
5. The group of CARs according to claim 1, wherein the target antigens specifically recognized by the antigen binding moieties of the group of CARs are naturally occurring cellular surface antigens or polypeptides, carbohydrates or lipids bound to naturally occurring cellular surface antigens.
7. A nucleic acid molecule comprising nucleotide sequences encoding the individual CAR molecules of a group of CARs according to claim 1, wherein the nucleic acid molecule is selected from DNA, RNA, or in vitro transcribed RNA.
8. A kit of nucleic acid molecules comprising nucleotide sequences encoding the individual CAR molecules of a group of CARs according to claim 1, wherein a nucleic acid molecule is selected from DNA, RNA, or in vitro transcribed RNA.
9. A vector or a kit of vectors comprising nucleotide sequences encoding the individual CAR molecules of a group of CARs according to claim 1, wherein the vector nucleic acid is DNA or RNA.
10. A cell modified in vitro or ex vivo with a nucleic acid molecule or a kit of nucleic acid molecules wherein the nucleic acid molecule is selected from DNA, RNA, or in vitro transcribed RNA to produce the individual CAR molecules of a group of CARs according to claim 1, or a kit comprising two or more of said modified cells.
11. A pharmaceutical preparation comprising the nucleic acid molecule according to claim 7.
16. A method of treatment of a cancer in an individual, wherein the method comprises:
i) genetically modifying NK cells or T lymphocytes obtained from the individual with at least one vector comprising nucleotide sequences encoding CAR molecules of the group of CARs of claim 1, wherein the antigen binding moieties of the group of CARs, are specific for target antigens on a cancer cell in the individual, and wherein said genetic modification is carried out in vitro or ex vivo; ii) introducing the genetically modified cells into the individual; and optionally iii) administering to the individual an effective amount of at least one regulating molecule for either inducing or reducing heterodimerization of the respective CAR molecules of the group, wherein the non- covalently complexed group of CARs, upon contact with a cancer cell expressing the respective target antigen combination at physiological expression levels, mediates activation of the genetically modified cell, which leads to killing of the cancer cell and thereby enables treating the cancer.
17. A method of treatment of a cancer in an individual, wherein the method comprises:
i) introducing the cell of claim 10 into the individual, said cell expressing antigen binding moieties of the group of CARs specific for target antigens on a cancer cell in the individual; and optionally
ii) administering to the individual an effective amount of at least one polypeptide that comprises at least an antigen binding moiety and is able to bind to a binding site in a CAR molecule of the group of CARs, and/or administering an effective amount of at least one regulating molecule heterodimerization of the respective CAR molecules of the group, wherein the non- covalently complexed group of CARs upon contact with a cancer cell expressing the respective target antigens mediates activation of the genetically modified cell, which leads to killing of the cancer cell and thereby enables treating the cancer.
19. The group of CARs of claim 1, wherein the antigen binding moieties of the group of CARs bind to at least two different target antigens present on a cell, on a solid surface, or a lipid bilayer.
20. The group of chimeric antigen receptors (CARs) consisting of two CAR molecules of claim 1, wherein the heterodimerization between the CAR molecules is regulated and initiated by binding of a regulating molecule under physiological conditions to at least one of the two CAR molecules.
21. The group of CARs of claim 20, wherein the regulating molecule comprises corticosterone.
The ‘522 claims teach as set forth above, but do not teach a CAR directed to EGFR or CA-125 .
Copper teaches an engineered cell comprising an expressed chimeric T-cell receptor (CAR) targeted to an antigen, said CAR having a Kd of between about 5 nM and about 500 nM relative to the antigen, wherein the antigen is EGFR or CA-125. See ¶¶ 0009-0011, 0014, 0015, 0031, 0106, 0128 and 0130 claims 1-3.
Cooper teaches that the antigen binding domain can be an scFv domain. See ¶¶ 0116-0119. The instant specification teaches that “. . . cysteines within Ig domains of antibody fragments (e.g. within scFvs), which form intramolecular disulfide bonds, may be present in the CAR molecules of the group of CARs according to the present invention. Since those cysteines in, e.g., scFvs are engaged in intramolecular disulfide bonds, they are not available for intermolecular disulfide bonds”. See paragraph bridging pp. 7-8 of the specification filed 5/17/2024. Thus, scFv binding domains containing cysteine are encompassed by the invention.
Cooper teaches that the hinge of the CAR can have the cysteine mutated by a proline or a serine substitution, or be truncated up to the first cysteine. See ¶ 0119.
Cooper teaches that the method is to control T-cell activation to the site of tumor based on the affinity of the scFv used in CAR design to mitigate activation of CAR+ T cells in response to low density of EGFR on normal tissue while mediating T-cell cytotoxicity in response to high EGFR density on tumor tissue. Advantages of this method are that (i) reduction of normal tissue toxicity is not associated with mitigated activity in response to tumor and (ii) activation/inhibition of T cells does not require recognition of multiple antigens, for which the stoichiometry of expression and binding to relative receptors must be tightly controlled. See ¶ 0104.
It would have been prima facie obvious at the time the invention was filed given that the level of skill in the art was high to combine the teachings of the ‘522 claims and Cooper and use the low affinity EGFR or CA-125 CARs as the CARs in the ‘522 claims because Cooper teaches that the CARs have the advantages of reduction in toxicity to normal tissues and the methods do not require the targeting of multiple antigens. Given the advantages taught by Cooper one would have been motivated with a reasonable expectation of success to use the low affinity EGFR or CA-125 CARs as the CARs in the ‘522 claims.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
9. Applicant argues that we traverse this rejection because present claims recite several features which are not recited in pending claims of 17/281,522.
Applicant argues that in view of the foregoing, the scope of present claims differs from the scope of claims in Application 17/281,522. The provisional double-patenting rejection must be withdrawn.
Applicant’s arguments have been considered, but have not been found persuasive because Applicant did not identify the features which they believe are not recited in pending claims of 17/281,522. Thus, the rejection of Claims 1, 2, and 5-16 is maintained for the reasons previously set forth and above.
Conclusion
10. All other objections and rejections recited in the Office Action of February 25, 2025 are withdrawn in view of Applicant’s arguments and amendments.
11. No claims allowed.
12. THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
13. Any inquiry concerning this communication or earlier communications from the examiner should be directed to PETER J REDDIG whose telephone number is (571)272-9031. The examiner can normally be reached on M-F 8:30-5:30 Eastern Time
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Janet L Epps-Smith can be reached on 571-272-0757. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/Peter J Reddig/
Primary Examiner, Art Unit 1642