DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
The claim listing filed March 9, 2023 is pending.
Claims 5, 21, 24, 25, 27-29, 33, 34, 36, 37, 39, and 42-44 are canceled.
Claims 1-4, 6-20, 22, 23, 26, 30-32, 35, 38, 40, 41, and 45 are pending.
Claims 1 and 35 are independent claims.
Applicant’s election without traverse of Group I (claims 1-4, 6-20, 22, 23, 26, 35, 38, 41, and 45, drawn to genetically modified cells; a method of producing the genetically modified cell; a recombinant nucleic acid expression construct; and a pharmaceutical composition); and the species of:
induced pluripotent stem cells (iPSC) as the type of cell,
SEQ ID NO: 14 as the CAR signal sequence,
SEQ ID NOs: 15 and 19 as the antigen-binding domain of a CAR that specifically recognizes CEA sequence,
SEQ ID NO: 24 as the CD3 zeta signaling domain sequence,
SEQ ID NO: 26 as the checkpoint inhibitory molecule,
dominant negative truncated PD-1 polypeptide as the checkpoint inhibitory molecule,
SEQ ID NO: 28 as the dominant negative truncated PD-1 polypeptide,
P2A as the polypeptide cleavage site disposed between the CAR polypeptide and the checkpoint inhibitory molecule,
IL-15 as the immune stimulatory cytokine,
SEQ ID NO: 29 as the signal sequence,
SEQ ID NO: 30 as the N-terminal IL15RA polypeptide sequence,
SEQ ID NO: 31 as the linking loop sequence, and
SEQ ID NO: 32 as the IL-15 polypeptide sequence
in the reply filed on December 1, 2025 is acknowledged.
Upon further consideration, the species election requirement with respect to specific amino acid sequences for the CAR (1) signal sequence, (2) anti-CEA antigen-binding domain, (3) immunoglobulin heavy chain extracellular constant region, (4) CD28 transmembrane domain, (5) CD28 signaling domain, and (6) CD3 zeta signaling as recited in claim 16 in the office action mailed on September 30, 2025 is withdrawn.
In view of the withdrawal of the restriction requirement regarding the specific amino acid sequences for the CAR, applicant(s) are advised that if any claim presented in a divisional application is anticipated by, or includes all the limitations of, a claim that is allowable in the present application, such claim may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application. Once the species restriction requirement of the specific amino acid sequences for the CAR is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable. See In re Ziegler, 443 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971). See also MPEP § 804.01.
Claims 30-32 and 40 have been withdrawn from further consideration pursuant to 37 CFR
1.142(b) as being drawn to nonelected inventions.
Claims 1-4, 6-20, 22, 23, 26, 35, 38, 41, and 45 are currently under consideration.
Nucleotide and/or Amino Acid Sequence Disclosures
This application contains sequence disclosures that are encompassed by the definitions for nucleotide and/or amino acid sequences set forth in 37 C.F.R. § 1.821 (a)(1) and (a)(2). However, this application fails to comply with the requirements of 37 C.F.R. § 1.821 through 1.825.
Specifically, the amino acid sequence of SEQ ID NO: 14 in the specification (page 51) and in SLIC are not the same. See sequence alignment below.
If two distinct sequences sequence were intended to be submitted, the Applicant must to provide a substitute computer readable form (CRF) copy of a "Sequence Listing" which includes all of the sequences that are present in the instant application and encompassed by these rules, a substitute paper copy of that "Sequence Listing", an amendment directing the entry of that paper copy into the specification, and a statement that the content of the paper and computer readable copies are the same and, where applicable, include no new matter, as required by 37 C.F.R. § 1.821 (e) or 1.821(f) or 1.821(g) or 1.825(b) or 1.825(d).
The instant specification will also need to be amended so that it complies with 37 C.F.R. § 1.821(d) which requires a reference to a particular sequence identifier (SEQ ID NO: ) be made in the specification and claims wherever a reference is made to that sequence. See M.P.E.P. 2422.04.
Query Match 89.6%; Score 90.5; DB 1; Length 20;
Best Local Similarity 95.0%;
Matches 19; Conservative 0; Mismatches 0; Indels 1; Gaps 1;
Specification 1 MGWSCIILFLVA-TATGVHS 19
|||||||||||| |||||||
SLIC 1 MGWSCIILFLVATTATGVHS 20
Priority
The instant Application is a 371 of PCT/EP2021/073363 filed 08/24/2021 and claims foreign priority to EP20205693.3 filed 11/04/2020 and EP20192398.4 filed 08/24/2020.
Specification
The specification is objected to as failing to provide proper antecedent basis for the claimed subject matter. See 37 CFR 1.75(d)(1) and MPEP § 608.01(o). Correction of the following is required: The SEQ ID NO: 14 recited in claim 16 is not recited anywhere in the specification. See above.
Claim Objections
Claim 1, 16, 17, 19, and 20 objected to because of the following informalities:
Claims 1, 16, and 20 have inappropriate punctuation throughout, namely the use of commas.
For example, claim 1 recites “Genetically modified cells, comprising…” in line 1 wherein the claim should recite “Genetically modified cells comprising…” without the comma before the word “comprising.”
Claim 16 recites “…an immunoglobulin heavy chain extracellular constant region of a CAR, according to SEQ ID NO 23, or a sequence with at least 80% sequence identity to SEQ ID NO 23…” in lines 9-11. The claim should instead recite “…an immunoglobulin heavy chain extracellular constant region of a CAR according to SEQ ID NO 23 or a sequence with at least 80% sequence identity to SEQ ID NO 23…” without the commas before the words “according” and “or.” Similar misuse of commas is seen throughout claim 16 and should also be corrected.
Claim 20 recites “…A signal sequence according to SEQ ID NO 29, or a sequence with at least 80% sequence identity to SEQ ID NO 29…” in lines 3 and 4. The claims should instead recite “…A signal sequence according to SEQ ID NO 29 or a sequence with at least 80% sequence identity to SEQ ID NO 29…” without the comma before the word “or.” Similar misuse of commas is seen throughout claim 20 and should also be corrected.
Claim 17 recites the term “adjacently” in line 4 where it should recite “adjacent.”
Claims 19 and 20 recite the phrase “A N-terminal IL15RA polypeptide” in line 4 and 5, respectively, where they should recite “An N-terminal IL15Rα polypeptide.”
Appropriate correction is required.
Claim Rejections - 35 USC § 112
Indefinite Language
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 3, 12-15, 16, 20, and 22 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.
Claim 3 recites “The genetically modified cells according to claim 1, wherein the first nucleic acid sequence region encoding the CAR comprises:(d.) a nucleic acid sequence encoding an extracellular antigen-binding domain that recognizes a CEA protein, said antigen-binding domain comprising an antibody or antibody fragment” in lines 1-5. It is unclear whether this “nucleic acid sequence encoding an extracellular antigen-binding domain that recognizes a CEA protein” is in addition to or are meant to be referring to that already recited in claim 1.
Amending the claim to recite: “The genetically modified cells according to claim 1, wherein the antigen-binding domain comprises an antibody or antibody fragment, and wherein the first nucleic acid sequence region encoding the CAR further comprises (a) a nucleic acid sequence encoding a transmembrane domain and (b) a nucleic acid sequence encoding an intracellular co-stimulatory domain” would obviate this part of the rejection.
Claims 12 and 14 recite the phrase "optionally" in line 2 which renders the claims indefinite because it is unclear whether the limitation(s) following the phrase is part of the claimed invention. See MPEP § 2173.05(d).
Claim 12 recites that the recombinant nucleic acid expression construct “optionally” comprises an additional nucleic acid sequence region encoding a chemokine receptor.
Claim 14 recites that the construct “optionally” comprises a further nucleic acid sequence region encoding a suicide gene.
Claim 13 recites “wherein the chemokine receptor is C-C chemokine receptor type 4 (CCR4)” in line 2. This limitation refers to the limitation in the “optionally” clause of claim 12 and is therefore also indefinite for the same reasons claim 12 is indefinite.
Claim 15 recites “The genetically modified cells according to claim 1, comprising a recombinant nucleic acid expression construct that encodes a CAR, said CAR comprising:” in lines 1-3 and the limitation “an antigen-binding domain of a CAR that specifically recognizes CEA” in line 5. It is unclear whether this “nucleic acid expression construct,” “CAR,” or “antigen-binding domain of a CAR that specifically recognizes CEA” are in addition to or are meant to be referring to those already recited in claim 1.
Amending the claim to recite: “The genetically modified cells according to claim 1, wherein the CAR comprises:” and “the antigen-binding domain of a CAR that specifically recognizes CEA” would obviate this part of the rejection.
Claim 16 similarly recites “The genetically modified cells according to claim 15, comprising a recombinant nucleic acid expression construct that encodes a CAR, said CAR comprising:” in lines 1-3 and the limitations: “a CAR signal sequence,” “an antigen-binding domain of a CAR that specifically recognizes CEA,” “an immunoglobulin heavy chain extracellular constant region of a CAR,” “a CD28 signaling domain,” “a transmembrane domain,” “a CD3 zeta signaling domain” in lines 4-17. It is unclear whether this “nucleic acid expression construct,” “CAR,” “CAR signal sequence,” “antigen-binding domain of a CAR that specifically recognizes CEA,” “immunoglobulin heavy chain extracellular constant region of a CAR,” “CD28 signaling domain,” “transmembrane domain,” “CD3 zeta signaling domain” are in addition to or are meant to be referring to those already recited in claim 15.
Furthermore, claim 16 also recites the limitation “an antigen-binding domain of a CAR that specifically recognizes CEA, according to SEQ ID NO 15 and SEQ ID NO 19, or a sequence with at least 80% sequence identity to SEQ ID NO 15 and 19” in lines 6-8. Based on the specification, SEQ ID NOs: 15 and 19 refer to the VL and VH regions of an anti-CEA antigen binding domain, respectively. As claim 16 is currently written it is unclear what SEQ ID NOs: 15 and 19 are referring to and if the antigen binding domain needs to comprise both SEQ ID NOs: 15 and 19.
Amending the claim to recite: “The genetically modified cells according to claim 15, wherein:
- the CAR signal sequence comprises an amino acid sequence according to SEQ ID NO: 14 or a sequence with at least 80% sequence identity to SEQ ID NO: 14;
- the antigen-binding domain comprises a variable light chain (VL) and a variable heavy chain (VH) region, wherein the VL and VH regions comprise an amino acid sequence according to SEQ ID NOs: 15 and 19, respectively, or wherein the VL and VH regions comprise an amino acid sequence with at least 80% sequence identity to SEQ ID NOs: 15 and 19, respectively;
- the immunoglobulin heavy chain extracellular constant region comprises an amino acid sequence according to SEQ ID NO: 23 or a sequence with at least 80% sequence identity to SEQ ID NO: 23;
- the CD28 signaling domain comprises an amino acid sequence according to SEQ ID NO: 24 or a sequence with at least 80% sequence identity to SEQ ID NO: 24;
-the transmembrane domain comprises an amino acid sequence according to SEQ ID NO: 25 or a sequence with at least 80% sequence identity to SEQ ID NO: 25; and
- the CD3 zeta signaling domain comprises an amino acid sequence according to SEQ ID NO: 26 or a sequence with at least 80% sequence identity to SEQ ID NO: 26” would obviate this part of the rejection.
Claim 20 recites the limitations “A signal sequence according to SEQ ID NO 29,” “A N-terminal IL15RA polypeptide according to SEQ ID NO 30,” “A linking loop sequence according to SEQ ID NO 31,” and “An IL-15 polypeptide according to SEQ ID NO 32” in lines 3-10. Similarly to claims 15 and 16, it is unclear whether this “signal sequence,” “N-terminal IL15RA polypeptide,” “linking loop sequence,” or “IL-15 polypeptide” are in addition to or are meant to be referring to those already recited in claim 19.
Amending the claim to recite: “The genetically modified cells according to claim 19, wherein: (g.) the signal sequence comprises an amino acid sequence according to SEQ ID NO: 29 or a sequence with at least 80% sequence identity to SEQ ID NO: 29;
(h.) the N-terminal IL15RA polypeptide comprises an amino acid sequence according to SEQ ID NO: 30 or a sequence with at least 80% sequence identity to SEQ ID NO: 30;
(i.) the linking loop sequence comprises an amino acid sequence according to SEQ ID NO: 31 or a sequence with at least 80% sequence identity to SEQ ID NO: 31; and
(j.) the IL-15 polypeptide comprises an amino acid sequence according to SEQ ID NO: 32 or a sequence with at least 80% sequence identity to SEQ ID NO: 32” would obviate this part of the rejection.
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 1-4, 6-20, 22, 23, 26, 35, 38, 41, and 45 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 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 instant claims are drawn to (1) genetically modified cells, comprising a recombinant nucleic acid expression construct encoding a CAR, said construct comprising:(a.) a first nucleic acid sequence region encoding a chimeric antigen receptor (CAR), said CAR comprising an extracellular antigen-binding domain that recognizes a carcinoembryonic antigen (CEA) protein, (b.) a second nucleic acid sequence region encoding a checkpoint inhibitory molecule, and (c.) a third nucleic acid sequence region encoding an immune stimulatory cytokine; (2) a recombinant nucleic acid expression construct; (3) a method for producing a genetically modified cell; and (4) a pharmaceutical composition.
The Applicant has disclosed a single construct that comprises an anti-CEA CAR, a checkpoint inhibitory molecule, and an immune stimulatory cytokine (e.g. see SEQ ID NO: 13 on page 50). It is noted that the Applicant has also disclosed a single set of six CDRs for the anti-CEA antigen binding domain of the CAR (e.g. see SEQ ID NOs: 16-18 and 20-22 on page 51).
When given the broadest reasonable interpretation in light of specification, the CARs of the instant invention are defined broadly to be any CAR molecule that comprises an anti-CEA antigen binding domain.
It is noted that the broadest claim (claim 1) does not indicate any specific structure for the genus of CARs comprising an anti-CEA antigen binding domain as claimed.
Claim 16 limits the CARs to those that comprise an antigen-binding domain comprising SEQ ID NOs: 15 and 19 or amino acid sequences with at least 80% identity to SEQ ID NOs: 15 and 19.
The guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, § 1 "Written Description" Requirement make clear that if a claimed genus does not show actual reduction to practice for a representative number of species, then the Requirement may be alternatively met by reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the genus (Federal Register, Vol. 66, No. 4, pages 1099-1111, January 5, 2001, see especially page 1106 column 3). In The Regents of the University of California v. Eli Lilly (43 USPQ2d 1398-1412) 19 F. 3d 1559, the court held that disclosure of a single member of a genus (rat insulin) did not provide adequate written support for the claimed genus (all mammalian insulins). In this same case, the court also noted:
“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. See Fiers, 984 F.2d at 1169-71, 25 USPQ2d at 1605-06 (discussing Amgen). It is only a definition of a useful result rather than a definition of what achieves that result. Many such genes may achieve that result. The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does “little more than outlin[e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate.”). Accordingly, 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.”
It is well known that antigen binding domains of CARs fall in three general categories, either single chain variable fragments (scFvs) derived from antibodies, Fab’s selected from libraries, or natural ligands that engage their cognate receptor (e.g. see Sadelain et al. Cancer Discov. 2013;3(4):388–398, page 389, left column, second paragraph under “CAR TARGETING”). Successful examples in each of these categories have been reported. scFvs derived from murine immunoglobulins are commonly used, as they are easily derived from well-characterized monoclonal antibodies. They, however, may prove to be more immunogenic than Fab’s derived from human libraries or invariant human ligands (e.g. see Sadelain et al. Cancer Discov. 2013;3(4):388–398, page 389, left column, second paragraph under “CAR TARGETING”).
Regarding CARs comprising antibody-derived antigen binding domains, artisans are well aware that knowledge of a given antigen (for instance CEA) provides no information concerning the sequence/structure of antibodies that bind the given antigen. For example, Edwards et al. (J. Mol. Biol., 2003, 334:103-118) teach that over 1,000 different antibodies to a single protein can be generated, all with different sequences spanning almost the entire heavy and light chain germline repertoire (42/49 functional heavy chain germlines and 33 of 70 V-lambda and V-kappa light chain germlines, and with extensive diversity in the HCDR3 region sequences (that are generated by VDJ germline segment recombination) as well, see entire document).
As such, it does not seem possible to predict the sequence/structure of an antibody that binds a given antigen, as there does not appear to be any common or core structure present within all antibodies that gives rise to the function of antigen binding. Further, given data, such as that of Edwards et al., indicating the diversity of sequences in a population of antibodies that bind to a given antigen, no number of species appears to reasonably representative of the breadth of the genus of antibodies that bind the given antigen.
It should be pointed out that it is well established in the art that the formation of an intact antigen-binding site requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three different complementarity determining regions, CDR1, 2 and 3, which provide the majority of the contact residues for the binding of the antibody to its target epitope. The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin (Janeway Jr et al., Immunology, 3rd Edition, 1997 Garland Publishing Inc., pages 3:1-3:11.see entire selection).
Thus, based upon the prior art, skilled artisans would reasonably understand that it is the structure of the CDRs within an antibody which gives rise to the functional property of antigen binding, the epitope to which said CDRs bind is an inherent property which appears to necessarily be present due to conservation of critical structural elements, namely the CDR sequences themselves.
This applies to the instant invention which is drawn to a genus of CARs comprising an anti-CEA antigen binding domain and subgenus that comprise amino acid sequences with at least 80% identity to SEQ ID NOs: 15 and 19.
As noted above, the Applicant has only disclosed a single construct that comprises an anti-CEA CAR, a checkpoint inhibitory molecule, and an immune stimulatory cytokine (e.g. see SEQ ID NO: 13 on page 50). Such a disclosure does not serve to provide sufficient written description of the claimed genus of CARs comprising an anti-CEA antigen binding domain. Further, the disclosure does not identify any specific structural features or combination of features which give rise to the function of binding to CEA. Additionally, there does not appear to be any reasonable shared structure present in the genus of recited CARs which gives rise to their functional activity. Ultimately, identifying a CAR simply on the basis of what it binds rather than by identifying the sequence/structure, namely the CDRs, of the CAR in question is generally insufficient to provide written description of the CAR in question.
This reasoning further applies to claim 16 which recites the limitation “an antigen-binding domain of a CAR that specifically recognizes CEA, according to SEQ ID NO 15 and SEQ ID NO 19, or a sequence with at least 80% sequence identity to SEQ ID NO 15 and 19” in lines 6-8. Claim 16 does not satisfy the written description requirement because the claim language allows for up to 20% variability in the amino acid sequence structure of the antigen-binding domain, including the CDRs, which would be expected to impact the functional binding activity of the antigen-binding domain based on the state of the prior art. Claim 16 is drawn to a broad subgenus of antigen-binding domain structures which are functionally defined by their ability to bind to CEA without reciting a corresponding structure expected to correlate with this ability as supported by Applicant’s disclosure.
Thus, there is insufficient written description for the breadth of CARs comprising an anti-CEA antigen binding domain as currently claimed, which are distinct and diverse and do not share a common structure that contributes to a common ability to bind to CEA.
Therefore, in view of the breadth of the claims and the limited disclosure, artisans would reasonably conclude that applicant was not in possession of the full breadth of CARs comprising an anti-CEA antigen binding domain encompassed by the claims at the time the instant application was filed.
Amending claims 1 and 35 to recite that the CAR comprises LCDRs1-3 and HCDRs1-3 as SEQ ID NOs: 16-18 and 20-22, respectively, or VL and VH domains as SEQ ID NOs: 15 and 19, respectively, would obviate this part of the rejection.
Enablement
Claims 1, 2, 4, 6-14, 17-20, 22, 23, 26, 35, 38, 41, and 45 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a chimeric antigen receptor (CAR) that comprises an antigen binding domain, a transmembrane domain, and an intracellular signaling domain, does not reasonably provide enablement for a CAR that (1) does not comprise a transmembrane domain or an intracellular signaling domain. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
The factors considered in determining whether a disclosure would require undue experimentation include:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In re Wands, 8 USPQ2d, 1400 (CAFC 1988) and MPEP § 2164.01.
Nature of the invention/Breadth of the claims
Independent claim 1 is drawn to genetically modified cells, comprising a recombinant nucleic acid expression construct encoding a CAR, said construct comprising:(a.) a first nucleic acid sequence region encoding a chimeric antigen receptor (CAR), said CAR comprising an extracellular antigen-binding domain that recognizes a carcinoembryonic antigen (CEA) protein, (b.) a second nucleic acid sequence region encoding a checkpoint inhibitory molecule, and (c.) a third nucleic acid sequence region encoding an immune stimulatory cytokine.
Dependent claims 3, 15, and 16 limit the genetically modified cells to those that comprise a CAR that comprises an antigen binding domain, a transmembrane domain, and an intracellular signaling domain.
Independent claim 35 is drawn to a recombinant nucleic acid expression construct encoding a chimeric antigen receptor (CAR), said construct comprising:(a.) a first nucleic acid sequence region encoding a chimeric antigen receptor (CAR), said CAR comprising an extracellular antigen-binding domain that recognizes a carcinoembryonic antigen (CEA) protein, (b.) a second nucleic acid sequence region encoding checkpoint inhibitory molecule, and (c.) a third nucleic acid sequence region encoding an immune stimulatory cytokine.
State of the prior art/Predictability of the art
Lindner et al. 2020 (Sci. Adv. 6: eaaz3223, 1-8) teach that the structure of a CAR minimally comprises an extracellular antigen recognition domain linked through a transmembrane domain to an intracellular activation domain or domains (e.g. see page 1, paragraph spanning left and right columns). Thus, the art ultimately teaches that a CAR must comprise three critical domains: (1) an antigen binding domain; (2) a transmembrane domain; and (3) an intracellular signaling domain.
Working examples/Guidance in the specification
The instant disclosure teaches that a transmembrane domain anchors the molecule in the cell membrane (e.g. see page 1, line 39). According to the present invention, a chimeric antigen receptor (CAR), comprises an extracellular antigen-binding domain, comprising an antibody or antibody fragment that binds a target antigen, a transmembrane domain, and an intracellular domain (e.g. see page 27, lines 17-19).
The "transmembrane domain" is the portion of the CAR that fuses the extracellular binding portion and intracellular signaling domain and anchors the CAR to the plasma membrane of the immune effector cell (e.g. see page 32, lines 12-14).
An "intracellular signaling domain," refers to the part of a CAR that participates in transducing the message of effective anti-CEA CAR binding to a human CEA polypeptide into the interior of immune effector cells to elicit effector cell function, e.g., activation, cytokine production, proliferation and cytotoxic activity, including the release of cytotoxic factors to the CAR-bound target cell, or other cellular responses elicited with antigen binding to the extracellular CAR domain (e.g. see page 32, lines 21-27).
The Applicant has also disclosed two CAR constructs: SEQ ID NOs: 13 and 33 both of which comprise an extracellular antigen-binding domain, a transmembrane domain, and an intracellular signaling domain (e.g. see pages 50-52).
It is noted that the applicant has not explicitly disclosed whether or not the CARs applied in the working examples spanning pages 54-56 of the specification comprise a transmembrane domain and an intracellular domain in addition to the anti-CEA extracellular domain.
Amount of experimentation necessary
The instant specification discloses two CAR constructs: SEQ ID NOs: 13 and 33 both of which comprise an extracellular antigen-binding domain, a transmembrane domain, and an intracellular signaling domain. However, the claims are not limited to CARs that comprise an antigen binding domain, a transmembrane domain, and an intracellular signaling domain. The claimed genus of CARs encompass those that do not comprise a transmembrane domain or an intracellular signaling domain. There is insufficient objective evidence that the disclosed CARs can be extrapolated to provide guidance and direction for how to make and/or use a CAR that does not comprise a transmembrane domain or an intracellular signaling domain.
Thus, based on the content of the disclosure in view of the prior art which teaches that a CAR must comprise three critical domains: (1) an antigen binding domain; (2) a transmembrane domain; and (3) an intracellular signaling domain, a skilled artisan, through extensive trial-and-error experimentation, would have to make a CAR that does not comprise a transmembrane domain or an intracellular signaling domain and then use the CAR in a genetically modified cell with a reasonable expectation of success.
However, as it has been noted above, the transmembrane domain is required to link the extracellular antigen recognition domain to the intracellular activation domain and anchor the CAR to the cell. Thus, this quantity of experimentation goes beyond what is considered “a reasonable degree of experimentation” and constitutes undue further experimentation in order to enable the CAR for the breadth of what is claimed.
Thus, the specification does not enable one of ordinary skill in the art to make and/or use what is claimed and therefore claims 1, 2, 4, 6-14, 17-20, 22, 23, 26, 35, 38, 41, and 45 are rejected under 35 U.S.C. 112(a) enablement.
Amending claims 1 and 35 to recite in the body of the claims that the CAR also comprises a transmembrane domain and intracellular domain in addition to the already recited antigen binding domain would obviate this part of the rejection.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 3, 4, 6-9, 12-15, 17, 18, 35, 38, and 41 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Adusumilli 2018 (WO 2018165228 A1).
Adusumilli teaches that a multicistronic vector was generated containing an MSLN-CAR, a dominant negative PD-1, and a membrane bound IL-12 construct separated by P2A peptide self-cleavage motifs under the control of a constitutive promoter, to constitutively express the three proteins in CAR T cells (e.g. see [00366] and FIG. 10, copied below). T cells were transduced with the multicistronic vector to express the MSLN-CAR, the dominant negative PD-1 and mIL-12, which were expressed by the T cells (e.g. see [00366]). Although the above construct taught by Adusumilli comprises an MSLN-CAR, Adusumilli also teaches that the CAR may instead target carcinoembryonic antigen (CEA) (e.g. see [00242]).
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Figure 10 depicts that the MSLN-CAR comprises an anti-MSLN single-chain variable fragment (scFv), a CD3ζ endodomain, a CD28 transmembrane domain, and a CD28 or 4- IBB cytoplasmic domain (as the costimulatory domain) (e.g. see [00102]).
Figure 10 of Adusumilli 2018 (WO 2018165228 A1).
Adusumilli also teaches that the extracellular domain of the CAR can be fused to a leader or a signal peptide that directs the nascent protein into the endoplasmic reticulum and subsequent translocation to the cell surface (e.g. see [0215]). Adusumilli also teaches that the CAR can also comprise a spacer region or sequence that links the domains of the CAR to each other, wherein the spacer region can be, for example, the CH2CH3 (constant) region of an immunoglobulin (e.g. see [0217]). It is noted that while the amino acid sequence of the CH2CH3 (constant) region of an immunoglobulin recited by Adusumilli is not disclosed, this constant region would inherently have an amino acid sequence with at least 80% identity to instant SEQ ID NO: 23, especially in the absence of evidence to the contrary.
Adusumilli also teaches that the PD-1 dominant negative form comprises amino acids 1 to 165 of a PD-1 sequence (SEQ ID NO: 33) such a PD-1 dominant negative form comprises signal peptide of PD-1, amino acids 1 to 20, and extracellular domain amino acids 21 to 165 (e.g. see [00277]). It is noted that amino acids 1 to 165 of SEQ ID NO: 33 are identical to instant SEQ ID NO: 28 (see sequence alignment below).
Adusumilli also teaches that their invention additionally provides pharmaceutical compositions comprising the cells of the invention (e.g. see [00355]). The pharmaceutical composition comprises a therapeutically effective amount of an immunostimulatory cell of the invention and a pharmaceutically acceptable carrier (e.g. see [00355]).
Alignment of instant SEQ ID NO: 28 and amino acids 1 to 165 of Adusumilli’s SEQ ID NO: 33:
Query Match 100.0%; Score 897; DB 1; Length 198;
Best Local Similarity 100.0%;
Matches 165; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MQIPQAPWPVVWAVLQLGWRPGWFLDSPDRPWNPPTFSPALLVVTEGDNATFTCSFSNTS 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MQIPQAPWPVVWAVLQLGWRPGWFLDSPDRPWNPPTFSPALLVVTEGDNATFTCSFSNTS 60
Qy 61 ESFVLNWYRMSPSNQTDKLAAFPEDRSQPGQDCRFRVTQLPNGRDFHMSVVRARRNDSGT 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 ESFVLNWYRMSPSNQTDKLAAFPEDRSQPGQDCRFRVTQLPNGRDFHMSVVRARRNDSGT 120
Qy 121 YLCGAISLAPKAQIKESLRAELRVTERRAEVPTAHPSPSPRPAGQ 165
|||||||||||||||||||||||||||||||||||||||||||||
Db 121 YLCGAISLAPKAQIKESLRAELRVTERRAEVPTAHPSPSPRPAGQ 165
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim 2 is rejected under 35 U.S.C. 103 as being unpatentable over Adusumilli 2018 (WO 2018165228 A1) in view of Hombach et al. 1999 (Gene Ther. 6, 300-304).
The teachings of Adusumilli are outlined in the 102 rejection above.
Adusumilli does not teach that the extracellular antigen-binding domain of the genetically modified cells recognizes a non-soluble form of the carcinoembryonic antigen (CEA) protein.
Hombach et al. teach that soluble antigen frequently present in high concentrations in the serum of cancer patients will block the receptor of grafted effector cells thus preventing tumor cell recognition and antigen-driven cellular activation upon specific receptor crosslinking (e.g. see page 300, paragraph spanning left and right columns). This limitation so far restricts the chimeric receptor approach to those patients with very low amounts of soluble antigen unlikely to prevent effector cell–tumor cell interaction. Malignant tumors, however, that express carcinoembryonic antigen (CEA) are frequently accompanied by high serum concentrations of soluble CEA. In this particular situation the application of the chimeric receptor-based strategy requires a receptor whose tumor cell recognition and effector cell activation is not affected by soluble antigen (e.g. see page 300, paragraph spanning left and right columns).
Hombach et al. further teach that they constructed an anti-CEA chimeric T cell receptor whose antigen binding domain has preferential binding specificity for the membrane-bound form of CEA (e.g. see paragraph spanning pages 300 and 301). Hombach et al. teach that their chimeric anti-CEA receptor is preferentially triggered by membrane-bound and immobilized CEA but not by soluble CEA and that this activity is not blocked by soluble CEA (e.g. see paragraph spanning pages 303 and 304).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Adusumilli to incorporate the teachings of Hombach et al. to include that the extracellular antigen-binding domain of the genetically modified cells recognizes a non-soluble form of the carcinoembryonic antigen (CEA) protein.
Given the known interference of soluble antigen in applying the chimeric receptor approach, the high serum concentrations of soluble CEA in malignant tumors, and the desire for a chimeric receptor-based strategy that is not affected by soluble antigen; it would have been obvious to a skilled artisan, with the goal of improving the efficacy of Adusumilli’s anti-CEA CAR T cell, to restrict its binding to the non-soluble form of CEA in order to avoid interference by soluble CEA with a reasonable expectation of success.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Claims 10 and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Adusumilli 2018 (WO 2018165228 A1) in view of Liu et al. 2017 (Leukemia. 32, 520-531).
The teachings of Adusumilli are outlined in the 102 rejection above.
Adusumilli does not teach that the immune stimulatory cytokine is IL-15 or that it maintains or enhances the activity, survival and/or number of immune cells within and/or in proximity to tumor tissue.
Liu et al. teach the transduction of cord blood (CB)-derived NK cells with a retroviral vector incorporating the genes for CAR-CD19, IL-15 and inducible caspase-9-based suicide gene (iC9), and demonstrated efficient killing of CD19-expressing cell lines and primary leukemia cells in vitro (e.g. see Abstract). Interleukin-15 (IL-15) production by the transduced CB-NK cells critically improved their function (e.g. see Abstract).
Liu et al. also teach that mature NK cells have a short lifespan with poor in vivo persistence both in humans and in mice and in vivo persistence of effector cells are crucial for sustained clinical responses (e.g. see page 530, fourth paragraph). Liu et al. therefore incorporated in their construct a gene encoding IL-15, a cytokine that drives NK cell expansion and persistence. This modification led to ectopic production of IL-15, which was predominantly antigen-driven, and to more robust activation of NK cells with enhanced in vivo proliferation, persistence and antitumor activity than that seen with CAR.19-transduced NK cells lacking IL-15. Although the latter could mediate an antitumor response, the effect was only transient, further emphasizing the importance of in vivo persistence of CAR-expressing NK cells for effective and durable antitumor immunity. Liu et al. also teach that exogenous administration of IL-15 was associated with significant toxicity when administered in combination with CAR.CD19-transduced CB-NK cells (but not NT NK cells), thus, supporting Liu et al.’s strategy to include IL-15 in the construct (e.g. see page 530, fourth paragraph).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Adusumilli to incorporate the teachings of Liu et al. to include that the immune stimulatory cytokine is IL-15 or that it maintains or enhances the activity, survival and/or number of immune cells within and/or in proximity to tumor tissue.
Given that IL-15 is known to drive NK cell expansion and persistence and that its incorporation into a CAR construct for ectopic production of IL-15 leads to more robust activation of NK cells with enhanced in vivo proliferation, persistence, and antitumor activity than that seen with NK cells lacking IL-15; it would have been obvious to a skilled artisan, with the goal of improving the proliferation, persistence, and antitumor activity of Adusumilli’s anti-CEA CAR T cell, to substitute the IL-12 gene in Adusumilli’s construct for an IL-15 gene with a reasonable expectation of success.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Claim 16 is rejected under 35 U.S.C. 103 as being unpatentable over Adusumilli 2018 (WO 2018165228 A1) in view of Xu et al. 2023 (US 20230203125 A1, Application No. 17/926,790 with an effective filing date of 05/22/2020) and Klein et al. 2020 (US 20200318105 A1, Application No. 16/906,931 with an effective filing date of 06/19/2020).
The teachings of Adusumilli are outlined in the 102 rejection above.
Adusumilli does not teach that the signal sequence has an amino acid sequence with at least 80% identity to SEQ ID NO: 14, the antigen-binding domain comprises amino acid sequences with at least 80% identity to SEQ ID NOs: 15 and 19, the CD28 signaling domain has an amino acid sequence with at least 80% identity to SEQ ID NO: 24, the transmembrane domain has an amino acid sequence with at least 80% identity to SEQ ID NO: 25, or the CD3zeta signaling domain has an amino acid sequence with at least 80% identity to SEQ ID NO: 26.
Xu et al. teach a CEA-targeting CAR with the following structure: ScFv(CEA)-hinge-TM-CD28-CD3ζ (e.g. see [0125]). According to Table 1, such a CAR comprises an amino acid sequence with at least 80% identity to those amino acid sequences recited in instant claim 16. See alignment below.
Query Match 93.5%; Score 2196; DB 1; Length 458;
Best Local Similarity 92.1%;
Matches 421; Conservative 0; Mismatches 0; Indels 36; Gaps 3;
Qy 22 DIQMTQSPSSLSASVGDRVTITCSTSSSVSYMHWYQQKPGKAPRLLIYSTSNLASGVPSR 81
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 DIQMTQSPSSLSASVGDRVTITCSTSSSVSYMHWYQQKPGKAPRLLIYSTSNLASGVPSR 60
Qy 82 FSGSGSGTDFTFTISSLQPEDIATYYCHQWSSYPTFGQGTKVEIKGSTSGSGKPGSGEGS 141
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 FSGSGSGTDFTFTISSLQPEDIATYYCHQWSSYPTFGQGTKVEIKGSTSGSGKPGSGEGS 120
Qy 142 TKGQVQLQESGPGLVRPSQTLSLTCTVSGFTISSGYSWHWVRQPPGRGLEWIGYIQYSGI 201
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 TKGQVQLQESGPGLVRPSQTLSLTCTVSGFTISSGYSWHWVRQPPGRGLEWIGYIQYSGI 180
Qy 202 TNYNPSLKSRVTMLVDTSKNQFSLRLSSVTAADTAVYYCAREDYDYHWYFDVWGQGSTVT 261
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 TNYNPSLKSRVTMLVDTSKNQFSLRLSSVTAADTAVYYCAREDYDYHWYFDVWGQGSTVT 240
Qy 262 VSS----------------------------------FWVLVVVGGVLACYSLLVTVAFI 287
||| |||||||||||||||||||||||
Db 241 VSSGAAAEWVLVVVGGVLACYSLLVTVAFIIDPKLCYFWVLVVVGGVLACYSLLVTVAFI 300
Qy 288 IFWVRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS-VKFSRSADAPAYQQ 346
||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||
Db 301 IFWVRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYQQ 360
Qy 347 GQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKP-RRKNPQEGLYNELQKDKMAEAYSEI 405
|||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||
Db 361 GQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEI 420
Qy 406 GMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPP 442
|||||||||||||||||||||||||||||||||||||
Db 421 GMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPP 457
Klein et al. teach that a CAR may comprise a signal peptide (e.g. see [0182]). Such a signal peptide will bring the protein to the surface of the cell membrane. The CAR the signal peptide may have the amino and amino acid sequence as shown in SEQ ID NO:78 (e.g. see [0182]). It is noted that SEQ ID NO: 78 has at least 80% sequence identity to instant SEQ ID NO: 14. See sequence alignment below.
Query Match 82.3%; Score 90.5; DB 1; Length 20;
Best Local Similarity 95.0%;
Matches 19; Conservative 0; Mismatches 0; Indels 1; Gaps 1;
Qy 3 MGWSCIILFLVA-TATGVHS 21
|||||||||||| |||||||
Db 1 MGWSCIILFLVATTATGVHS 20
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Adusumilli to incorporate the teachings of Xu et al. and Klein et al. to include that the signal sequence has an amino acid sequence with at least 80% identity to SEQ ID NO: 14, the antigen-binding domain comprises amino acid sequences with at least 80% identity to SEQ ID NOs: 15 and 19, the CD28 signaling domain has an amino acid sequence with at least 80% identity to SEQ ID NO: 24, the transmembrane domain has an amino acid sequence with at least 80% identity to SEQ ID NO: 25, and the CD3zeta signaling domain has an amino acid sequence with at least 80% identity to SEQ ID NO: 26.
Given that Xu et al. describes an anti-CEA CAR construct that incorporates an anti-CEA ScFv, a CD28TM, a CD28 co-stimulatory domain, and a CD3ζ intracellular signaling domain all with amino acid sequences with at least 80% sequence identity to those recited in instant claim 16, and Klein et al. teach a signal peptide for a CAR that has an amino acid sequence with at least 80% identity to SEQ ID NO:14 which is meant to bring the CAR to the surface of the cell membrane; it would have been obvious to a skilled artisan to include these amino acid sequences in Adusumilli’s anti-CEA CAR with a reasonable expectation of success.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Claims 19 and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Adusumilli 2018 (WO 2018165228 A1) in view of Liu et al. 2017 (Leukemia. 32, 520-531) and Bergamaschi et al. 2009 (J. Immunol. 183(5):3064–3072).
The teachings of Adusumilli are outlined in the 102 rejection above.
Adusumilli does not teach that the immune stimulatory cytokine comprises: (c.) A signal sequence; (d.) A N-terminal IL15RA polypeptide; (e.) A linking loop sequence; and (f.) An IL-15 polypeptide.
The teachings of Liu et al. are outlined in the 103 rejection to claims 10 and 11 above.
Bergamaschi et al. teach that the two known isoforms of IL-15 contain either a long signal peptide (LSP) or a short signal peptide (SSP) (e.g. see Abstract). Several experiments have suggested that the simultaneous expression of IL-15Rα in the same cell is necessary for the production and secretion of IL-15 under physiological conditions (e.g. see page 3064, right column, third paragraph). Intracellular interaction between IL-15 and IL-15Rα results in the generation of a stable complex that can trans-locate to the cell membrane, be cleaved, and released as bioactive heterodimeric cytokine. Studies suggest that the IL-15/IL-15Rα complex, either on the surface of the cells or as a soluble heterodimer, is the most active form of IL-15 (e.g. see page 3064, right column, third paragraph).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Adusumilli to incorporate the teachings of Liu et al. and Bergamaschi et al. to include that the immune stimulatory cytokine comprises: (c.) A signal sequence; (d.) A N-terminal IL15RA polypeptide; (e.) A linking loop sequence; and (f.) An IL-15 polypeptide.
Given that the incorporation of IL-15 into a CAR construct for ectopic production of IL-15 leads to more robust activation of NK cells with enhanced in vivo proliferation, persistence, and antitumor activity than that seen with NK cells lacking IL-15, IL-15 is known to contain a signal peptide, and simultaneous expression of IL-15Rα in the same cell is necessary for the production and secretion of IL-15 under physiological conditions; it would have been obvious to a skilled artisan, with the goal of improving the proliferation, persistence, and antitumor activity of Adusumilli’s anti-CEA CAR T cell, to substitute the IL-12 gene in Adusumilli’s construct for an IL-15 gene with a reasonable expectation of success. Furthermore, it would also be obvious to a skilled artisan to include an IL-15 signal sequence and IL-15Rα in the construct given the well-known expression of a leader sequences for this cytokine and the stability IL-15Rα offers when in complex with IL-15. It is noted that it would be obvious to a skilled artisan to also include a linker between IL-15 and IL-15Rα in order to promote dimerization.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Claim 23 is rejected under 35 U.S.C. 103 as being unpatentable over Adusumilli 2018 (WO 2018165228 A1) in view of Li et al. 2018 (Cell Stem Cell 23, 181–192).
The teachings of Adusumilli are outlined in the 102 rejection above.
Adusumilli does not teach that the genetically modified cells are induced pluripotent stem cells (iPSC).
Li et al. teach that the design of iPSC-derived CAR-NK cells (e.g. see Abstract). Use of iPSCs (or hESCs) for NK cell production provides a more efficient means for gene modification compared with primary NK cells isolated from peripheral blood (e.g. see page 190, left column, third paragraph). In addition to CAR expression, other modifications, such as deletion of inhibitory receptors or expression of cytokines, can potentially be engineered into these cells to further enhance anti-tumor activity. Additionally, this can be done as a one-time genetic modification event rather than requiring patient-specific gene modification, as done with current CAR-T cell studies. iPSC-derived NK cells can also be produced on a large scale as a standardized cell product. This will allow multiple doses to be administered rather than the single cell dosing done with current CAR-T cell-based therapies. This repeat dosing, possibly combined with cycles of chemotherapy, may mediate more effective therapy against refractory solid tumors (e.g. see page 190, left column, third paragraph).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Adusumilli to incorporate the teachings of Li et al. to include that the genetically modified cells are induced pluripotent stem cells (iPSC).
Given practicality of using iPSCs to make iPSC-derived CAR-NK cells because of their efficient means for gene modification and their ability to be used for repeat dosing; it would have been obvious to a skilled artisan, with the goal of improving the efficiency of making and applicability of Adusumilli’s anti-CEA CAR T cell, to use an iPSC instead of a T cell with a reasonable expectation of success.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Claim 26 is rejected under 35 U.S.C. 103 as being unpatentable over Adusumilli 2018 (WO 2018165228 A1) in view of Li et al. 2018 (Cell Stem Cell 23, 181–192) and Germeroth 2021 (US 20210284965 A1, Application No. 17/259,900 with an effective filing date of 07/13/2018).
The teachings of Adusumilli are outlined in the 102 rejection above.
Adusumilli does not teach that the genetically modified cells are induced pluripotent stem cell (iPSC) line ND50039.
The teachings of Li et al. are outlined in the 103 rejection to claim 23 above.
Germeroth teaches the pluripotent stem cells ND50039 of the NINDS Human Cell and Data Repository (e.g. see [0020]).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Adusumilli to incorporate the teachings of Li et al. and Germeroth to include that the genetically modified cells are induced pluripotent stem cell (iPSC) line ND50039.
Given practicality of using iPSCs to make iPSC-derived CAR-NK cells because of their efficient means for gene modification, their ability to be used for repeat dosing, and that ND50039 is a well-known iPSC line; it would have been obvious to a skilled artisan, with the goal of improving the efficiency of making and applicability of Adusumilli’s anti-CEA CAR T cell, to use an iPSC, and specifically the ND50039 cell line, instead of a T cell with a reasonable expectation of success.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Claim 45 is rejected under 35 U.S.C. 103 as being unpatentable over Adusumilli 2018 (WO 2018165228 A1) in view of Zhang et al. 2018 (BMC Biotechnology, 18(4), 1-9).
The teachings of Adusumilli are outlined in the 102 rejection above.
Adusumilli does not teach that the nucleic acid construct is transferred or delivered into the cell in vitro using electroporation.
Zhang et al. teach electroporation is a faster, theoretically safer, and more economical method relative to viral-particle-based delivery and has been established for T cells (e.g. see page 2, left column, second paragraph).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Adusumilli to incorporate the teachings of Zhang et al. to include that the nucleic acid construct is transferred or delivered into the cell in vitro using electroporation.
Given that electroporation is a fast, theoretically safe, and economical method; it would have been obvious to a skilled artisan to transfer the nucleic acid of claim 38 by electroporation with a reasonable expectation of success.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
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 1, 3, 4, 6-9, 10-15, 17-20, 22, 23, 26, 35, 38, 41, and 45 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 5-13, 18-21, 24-26, 29, 37, 40, and 44 of Co-pending U.S. Application No. 18/042,550 (the ‘550 Application) in view of Holzinger and Abken 2017 (Cancer Immunol Immunother. 66, 1505-1507).
The instant claims are drawn to genetically modified cells, comprising a recombinant nucleic acid expression construct encoding a CAR, said construct comprising:(a.) a first nucleic acid sequence region encoding a chimeric antigen receptor (CAR), said CAR comprising an extracellular antigen-binding domain that recognizes a carcinoembryonic antigen (CEA) protein, (b.) a second nucleic acid sequence region encoding a checkpoint inhibitory molecule, and (c.) a third nucleic acid sequence region encoding an immune stimulatory cytokine; a recombinant nucleic acid expression construct; a method for producing a genetically modified cell; and a pharmaceutical composition.
The claims in the ‘550 Application are drawn to a recombinant nucleic acid expression construct, comprising: (a.) a first nucleic acid sequence region encoding a chimeric antigen receptor (CAR), (b.) a second nucleic acid sequence region encoding a checkpoint inhibitory molecule, and (c.) a third nucleic acid sequence region encoding an immune stimulatory cytokine; a CAR; genetically modified cells; a method for producing genetically modified cells; and a pharmaceutical composition.
The claims in the ‘550 Application differ from the instant invention by failing to recite that the CAR binds CEA.
Holzinger and Abken teach that targeting CEA has the advantage that healthy cells expose CEA in a polarized fashion on the luminal side, while cancer cells express the antigen over the entire cell surface (e.g. see page 1505, paragraph spanning the left and right columns). As a consequence, CEA on cancer cells is recognized by CAR T cells which become activated and finally eliminate the targeted cancer cells, while healthy cells with luminal CEA remain invisible to CAR T cells (e.g. see page 1505, paragraph spanning the left and right columns). Holzinger and Abken teach also teach that CEA can be safely targeted by CAR T cells (e.g. see page 1507, right column).
It would be obvious to one of ordinary skill in the art to have modify the claims in the ‘550 Application to incorporate the teachings of Holzinger and Abken to include that the CAR binds CEA.
Given that specific expression of CEA on cancer cell and that CEA is known to be a good target for Car T cell therapy; it would be obvious to a skilled artisan to specifically target CEA with the ‘550 Application’s CAR with a reasonable expectation of success.
Therefore, the claims in the ‘550 Application would render the instant claims obvious.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 2 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 5-13, 18-21, 24-26, 29, 37, 40, and 44 of Co-pending U.S. Application No. 18/042,550 (the ‘550 Application) in view of Holzinger and Abken 2017 (Cancer Immunol Immunother. 66, 1505-1507), as applied to claim 1, and further in view of Hombach et al. 1999 (Gene Ther. 6, 300-304).
The combined teachings of the claims of the ‘550 Application. in view of Holzinger and Abken pertaining to claim 1 and the rationale for combining them are outlined in the NSDP rejection above.
The combined reference teachings differ from the instant invention by not teaching that the extracellular antigen-binding domain of the genetically modified cells recognizes a non-soluble form of the carcinoembryonic antigen (CEA) protein.
The teachings of Hombach et al. are outlined in the 103 rejection of claim 2 above.
It would be obvious to one of ordinary skill in the art to modify the combined teachings of the claims of the ‘550 Application. in view of Holzinger and Abken as applied to claim 1 and to incorporate the teachings of Hombach et al. to include that the extracellular antigen-binding domain of the genetically modified cells recognizes a non-soluble form of the carcinoembryonic antigen (CEA) protein.
Given the known interference of soluble antigen in applying a chimeric receptor approach, the high serum concentrations of soluble CEA in malignant tumors, and the desire for a chimeric receptor-based strategy that activation is not affected by soluble antigen; it would be obvious to a skilled artisan, with the goal of improving the efficacy of the anti-CEA CAR taught by the ‘550 Application in view of Holzinger and Abken, to restrict its binding to the non-soluble form of CEA in order to avoid interference by soluble CEA with a reasonable expectation of success.
Combining prior art elements according to known methods to yield predictable results is obvious to one of ordinary skill in the art (see MPEP § 2143(A)). From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention.
Therefore, the claims in the ‘550 Application would render the instant claims obvious.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 16 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 5-13, 18-21, 24-26, 29, 37, 40, and 44 of Co-pending U.S. Application No. 18/042,550 (the ‘550 Application) in view of Holzinger and Abken 2017 (Cancer Immunol Immunother. 66, 1505-1507), as applied to claims 1 and 15, and further in view of Xu et al. 2023 (US 20230203125 A1, Application No. 17/926790 with an effective filing date of 05/22/2020) and Klein et al. 2020 (US 20200318105 A1, Application No. 16/906931 with an effective filing date of 06/19/2020).
The combined teachings of the claims of the ‘550 Application. in view of Holzinger and Abken pertaining to claim 1 and the rationale for combining them are outlined in the NSDP rejection above.
The combined reference teachings differ from the instant invention by not teaching that the signal sequence has an amino acid sequence with at least 80% identity to SEQ ID NO: 14, the antigen-binding domain comprises amino acid sequences with at least 80% identity to SEQ ID NOs: 15 and 19, the CD28 signaling domain has an amino acid sequence with at least 80% identity to SEQ ID NO: 24, the transmembrane domain has an amino acid sequence with at least 80% identity to SEQ ID NO: 25, or the CD3zeta signaling domain has an amino acid sequence with at least 80% identity to SEQ ID NO: 26.
The teachings of Xu et al. and Klein et al. are outlined in the 103 rejection of claim 16 above.
It would be obvious to one of ordinary skill in the art to modify the combined teachings of the claims of the ‘550 Application. in view of Holzinger and Abken as applied to claims 1 and 15 and to incorporate the teachings of Xu et al. and Klein et al. to include that the signal sequence has an amino acid sequence with at least 80% identity to SEQ ID NO: 14, the antigen-binding domain comprises amino acid sequences with at least 80% identity to SEQ ID NOs: 15 and 19, the CD28 signaling domain has an amino acid sequence with at least 80% identity to SEQ ID NO: 24, the transmembrane domain has an amino acid sequence with at least 80% identity to SEQ ID NO: 25, and the CD3zeta signaling domain has an amino acid sequence with at least 80% identity to SEQ ID NO: 26.
Given that Xu et al. describes an anti-CEA CAR construct that incorporates an anti-CEA ScFv, a CD28TM, a CD28 co-stimulatory domain, and a CD3ζ intracellular signaling domain all with amino acid sequences with at least 80% sequence identity to those recited in instant claim 16; and Klein et al. teach a signal peptide for a CAR that has an amino acid sequence with at least 80% identity to SEQ ID NO:14 and it is meant to bring the CAR to the surface of the cell membrane; it would have been obvious to a skilled artisan to include these amino acid sequences in the anti-CEA CAR taught by the ‘550 Application in view of Holzinger and Abken with a reasonable expectation of success.
Combining prior art elements according to known methods to yield predictable results is obvious to one of ordinary skill in the art (see MPEP § 2143(A)). From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention.
Therefore, the claims in the ‘550 Application would render the instant claims obvious.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
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/GRACE H LUNDE/Examiner, Art Unit 1641
/CHUN W DAHLE/Primary Examiner, Art Unit 1641