DETAILED ACTION
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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 03/09/2026 has been entered.
Status of Claims
The amended claims filed 03/09/2026 are acknowledged and entered.
Claims 17, 20, 98, and 99 have been amended
Claims 1-16, 18, 19, 21-27, 29-31, 33, 34, 36-38, 40-43, 45-53, 55-64, 68-70, 72-89, 91, 94-97, and 100-105 were previously cancelled.
Claims 93 is withdrawn
Claims 17, 20, 28, 32, 35, 39, 44, 54, 65-67, 71, 90, 92, 98, 99, 106, and 107 are pending and examined on their merits.
Response to Amendment
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office Action.
Claim Objections
Claim 35, 39, 44, 65-67, 71 and 92 are objected to because of the following informalities:
Claim 35 recites: “…comprises a transmembrane region of CD4, CD8, or CD28.”. The recitation should be " comprises a transmembrane region from one of CD4 CD8, or CD28." for clarity.
Claim 39 recites: “…..cytoplasmic signaling domain, wherein the intracellular signaling region…”. The recitation should be “..cytoplasmic signaling domain and wherein the intracellular signaling region…”.
Claim 44 recites needs the period after ICOS. a signaling portion thereof is a functional signaling domain, which is already stated.
Claims 65-67 and 71 need the term isolated after A or An in the recitation for clarity and to prevent the claims reading on transgenes and transgenic cells in transgenic animals. An example would be the recitation of Claim 65: “A polynucleotide encoding the chimeric antigen receptor…” to be recited as ““An isolated polynucleotide encoding the chimeric antigen receptor…”
Claim 92 recitation “…introducing a nucleic acid into a cell, wherein…” needs to be recited as ““…introducing a nucleic acid into a cell in vitro or ex vivo, wherein…” for clarity and to be consistent with claim 90.
Appropriate correction are required.
Claim Rejections - 35 USC § 103 - Withdrawn
The rejections of claims 17, 20, 28, 32, 35, 39, 44, 54, 65-67, 71, 90, 92, 98, 99, 106, and 107 under 35 U.S.C. 103 as being unpatentable over Wu (previously cited) in view of Rabello (previously cited) and John et al. (previously cited ) in view of Applicant’s amendments to claims 17, 20, 98, and 99.
The rejections of claims 17, and 54 under 35 U.S.C. 103 as being unpatentable over Wu (previously cited) in view of Liu (previously cited) in view of Applicant’s amendments to claims 17.
New Rejections Based on Amendments
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. Claims 17 and 98-99 and 107 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 17 recites the limitation: “…wherein the antigen-binding domain comprises a heavy chain variable region (VH) and a light chain variable region (VL), and the VH comprises VH complementarity determining regions (CDRs) 1, 2, and 3 and the VL comprises VL CDRs 1, 2, and 3; wherein the VH CDRs 1, 2, and 3 comprise amino acid sequences set forth in SEQ ID NOs: 69, 70, and 71, respectively, and the VL CDRs 1, 2, and 3 comprise amino acid sequences set forth in SEQ ID NOs: 72, 73, and 74, respectively;…”. This recitation needs to be modified for clarity so it reads on the full length sequences: “…. wherein the antigen-binding domain comprises a heavy chain variable region (VH) and a light chain variable region (VL), and the VH comprises VH complementarity determining regions (CDRs) 1, 2, and 3 and the VL comprises VL CDRs 1, 2, and 3; wherein the VH CDRs 1, 2, and 3 comprise the amino acid sequences set forth in SEQ ID NOs: 69, 70, and 71, respectively, and the VL CDRs 1, 2, and 3 comprise the amino acid sequences set forth in SEQ ID NOs: 72, 73, and 74, respectively;….”
Claims 98-99 and 107 recites the limitation "An anti-ALPP antibody or antigen-binding fragment thereof comprising:….”. This limitation is unclear because “antibody” is defined to include monoclonal (mAb), polyclonal antibodies (pAb) etc. and can also refer to any antigen-binding molecule that contains at least one claimed CDR. Therefore, the claim encompasses polyclonal antibodies with at least 1 claimed CDR. However, polyclonal antibodies have many and different antibody species. The CDRs or variable regions could be found in one molecule in the pAb or two. These presence of multiple structural interpretations renders the claims indefinite. Recitation’s clarity is improved by the following changes: adding “monoclonal” to the limitation. So, the recitation reads: “A monoclonal anti-ALPP antibody or antigen-binding fragment thereof comprising …….” In claim 98.
In addition, the claim currently recites “…a heavy chain variable region (VH) comprising VH complementarity determining regions (CDRs) 1, 2, and 3, wherein the VH CDRs 1, 2, and 3 comprise amino acid sequences set forth in SEQ ID NOs: 69, 70, and 71, respectively; and a light chain variable region (VL) comprising VL CDRs 1, 2, and 3, wherein the VL CDRs 1, 2, and 3 comprise amino acid sequences set forth in SEQ ID NOs: 72, 73, and 74, respectively….” This recitation needs to be modified for clarity: “….a heavy chain variable region (VH) comprising VH complementarity determining regions (CDRs) 1, 2, and 3, wherein the VH CDRs 1, 2, and 3 comprise the amino acid sequences set forth in SEQ ID NOs: 69, 70, and 71, respectively; and a light chain variable region (VL) comprising VL CDRs 1, 2, and 3, wherein the VL CDRs 1, 2, and 3 comprise the amino acid sequences are set forth in SEQ ID NOs: 72, 73, and 74, respectively; and …”
Appropriate correction is required.
The following is a quotation of the first paragraph of 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.
6. Claims 65-67, 71, 90 and 92 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 an isolated or purified polynucleotide, vector and/or a host cell, does not reasonably provide enablement for said non-isolated polynucleotide, vector and/or a host cell, which reads upon a transgenic animal or a transgene therein. 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 legal considerations that govern enablement determinations pertaining to undue experimentation have been clearly set forth. Enzo Biochem, Inc., 52 U.S.P.Q.2d 1129 (C.A.F.C. 1999). In re Wands, 8 U.S.P.Q.2d 1400 (C.A.F.C. 1988). See also MPEP § 2164.01(a) and § 2164.04. Ex parte Forman 230 U.S.P.Q. 546 (PTO Bd. Pat. App. Int., 1986). The courts concluded that several factual inquiries should be considered when making such assessments including: the quantity of experimentation necessary, the amount of direction or guidance presented, the presence or absence of working examples, the nature of the invention, the state of the prior art, the relative skill of those in that art, the predictability or unpredictability of the art and the breadth of the claims. In re Rainer, 52 C.C.P.A. 1593, 347 F.2d 574, 146 U.S.P.Q. 218 (1965). The disclosure fails to provide adequate guidance pertaining to a number of these considerations as follows:
Nature of the invention/Breadth of the claims. Applicant broadly claims polynucleotide or a vector or a host cell. Under broadest reasonable interpretation, the claims read on a cell within a transgenic animal or a transgene therein, given that the term "isolated" is not denoted in describing the host cell, nucleic acid, or vector.
State of the prior art/Predictability of the art. With respect to the unisolated host cells and transgenes as “nucleic acids” or “vectors “of the instant claims discussed above, the state of the art at the time of filing was such that one of skill in the art could not predict the phenotype of transgenics. The art of transgenic animals has for many years stated that the unpredictability lies, in part, with the site or sites of transgene integration into the target genome and that "the position effect" as well as unidentified control elements are recognized to cause aberrant expression of a transgene and possible silencing of host genes, which result in undesirable phenotypes and/or additional health issues in the animal. The elements of the particular construct used to make transgenic animals are also held to be critical, and they must be designed case by case without general rules to obtain good expression of a transgene in the host. Viral vectors, such as Adeno-associated virus (AAV), adenovirus (AdV), and lentiviral/retroviral vectors, can transfer larger amounts of genetic information to a host, but some vectors cannot carry all the required genetic structures for proper expression (e.g. entire gene plus extensive regulatory elements) and certain viral vectors can cause uncontrolled, random integration, which increases the risk of tumorigenesis and inconsistent expression. (See e.g. National Academies of Sciences, Engineering, and Medicine; Division on Earth and Life Studies; Food and Nutrition Board; Board on Agriculture and Natural Resources; Committee on Heritable Genetic Modification in Food Animals. Heritable Genetic Modification in Food Animals. Washington (DC): National Academies Press (US); 2025 Apr 23. 3, Potential Hazards to Animals and Consumers.; Park F. Lentiviral vectors: are they the future of animal transgenesis? Physiol Genomics. 2007 Oct 22;31(2):159-73. Epub 2007 Aug 7.; Shakweer WME, Krivoruchko AY, Dessouki SM, Khattab AA. A review of transgenic animal techniques and their applications. J Genet Eng Biotechnol. 2023 May 9;21(1):55.). Therefore, the field of transgenics was and remains highly unpredictable.
Working examples/Guidance in the Specification. No working example of a transgenic animal is disclosed in the specification. The specification provides guidance towards the generation and use of a/an isolated/purified polynucleotide, vector and/or a host cell
Amount of experimentation necessary. At the time of filing, the phenotype of a transgene and transgenic cell contained within any animal was unpredictable. The claims as written, encompassing a transgene and cell in a transgenic animal, is not adequately described in the specification as to prevent excessive experimentation by the public to generate and use the invention. Applicants can obviate the instant rejection by amending the claim to clarify that the polynucleotide, vector and/or a host cell is not within a transgenic animal by utilizing the term "isolated" before the recitation of said polynucleotide, vector and/or a host cell. Applicant may consider using purified in such claims if description is appropriate for such a term and it is not redefined away from standard meaning. Method claims using these products should also carry the appropriate adjectives above.
In view of the lack of the predictability of the art to which the invention pertains as evidenced by the art above, the lack of guidance and direction provided by Applicant, and the absence of working examples, undue experimentation would be required to make and use the transgenes and transgenic animals commensurate in scope with the claimed invention with a reasonable expectation of success. Thus, the claims are rejected here.
For the reasons discussed above, it would require undue experimentation for one skilled in the art to make and/or use the claimed products.
Claim 54 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a CAR comprising SEQ ID NO. 26, does not reasonably provide enablement for just any variant of SEQ ID NO. 26 with just any transmembrane domain and intracellular signaling domain mutations. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make or use the invention commensurate in scope with these claims.
The breadth of the claim is the CAR of claim 17 comprising at least 90% identity to SEQ ID NO. 26. This permits up to 50 mutations in the transmembrane and/or intracellular signaling domains thereof. At its full breadth, it must carry some mutations outside the VH and VL domains.
The nature of the invention is an anti-ALPP CAR.
The level of skill of one skilled in this art is high.
The specification provides mutations of Fc regions on page 35. However, CARs do not carry such domains. No specifically contemplated transmembrane or intracellular signaling domain mutations are taught it appears in the specification.
The prior art makes clear that peptide mutation is unpredictable and changes in protein sequence must be made and tested to establish variant function. Ju (Proceedings of the National Academy of Sciences, U.S.A., Vol. 88, Pg. 2658-2662, 1991) teaches that the interleukin 1 receptor (IL-1R) antagonist IL-1ra is a naturally occurring protein with no agonist activity in vitro or in vivo (Abstract). However, substitution of a single amino acid lysine145 to aspartic acid changes the property of this peptide to a partial agonist of IL-1R (Abstract). Thus, even a single substitution can change the biological property of a peptide. With respect to the transmembrane and signaling domains of CARs, such as CD3, the prior art shows undesired effects of their mutation. Brazin (Immunity, Vol. 49, Pg. 829-841, 2018) teaches that mutation in the transmembrane at residues 251 and 256 can lead to an activated transcriptome (Abstract) while mutations to CD3 and TCRalpha connecting peptide attenuated signal transduction (Abstract). Neither attenuation nor constitutive activation are desirable in a CAR and so it is clear that not just any mutation of CARs is tolerable or desirable and the claim is therefore not enabled to its full scope.
Claim 54 is 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.
As discussed above, the claim is the CAR of claim 17 comprising at least 90% identity to SEQ ID NO. 26. This permits up to 50 mutations in the transmembrane and/or intracellular signaling domains thereof. At its full breadth, it must carry some mutations outside the VH and VL domains. The works of Ju and Brazin discussed above, all said discussions incorporated here, make clear that a PHOSITA would not assume anyone was in possession of such mutation breadth without evidence to include making and testing the variants. No such variants appear to have been taught in the instant disclosure.
“[T]he purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent specification.’” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.04.
An applicant may show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that applicant was in possession of the claimed invention, 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. Enzo Biochem, 323 F.3d at 964, 63 USPQ2d at 1613.
Furthermore, to satisfy the written description requirement for the genus antibody with specific epitope, and by extension the similar molecule of CAR, Applicant must adequately describe representative species to reflect the structural diversity of the claimed genus. See Eli Lilly, 119 F.3d at 1568 (“[N]aming 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.”); Fiers v. Revel, 984 F.2d 1164, 1171 (Fed. Cir. 1993) (“Claiming all DNA[s] that achieve a result without defining what means will do so is not in compliance with the description requirement; it is an attempt to preempt the future before it has arrived.”).
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, 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 claimed genus. A “representative number of species” means that the species which are adequately described are representative of the entire genus. See, e.g., AbbVie Deutschland GMBH v. Janssen Biotech, 759 F.3d 1285, 111 USPQ2d 1780 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, as here, in which the CAR transmembrane domain and intracellular signaling domain can carry mutations of any nature, one must describe a sufficient variety of species to reflect the variation within the genus. The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure “indicates that the patentee has invented species sufficient to constitute the gen[us].” See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615. Here, Applicant provides only SEQ ID NO. 26 to represent the genus and so the claim clearly fails the written description requirement. Applicant has taught a species and not a genus.
Conclusion
Claims 17, 54, 65-67, 71, 90, 92, 98-99 and 107 stand rejected.
Claims 35, 39, 44, 65-67, 71 and 92 are objected to because of informalities.
Claims 20, 28, 32, 35, 39, 44, 65-67, 71, 90, 92, 98-99, 106, and 107 are objected to because they depend on a rejected claim.
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/IMMA BARRERA/
Examiner, Art Unit 1671
/Michael Allen/ Supervisory Patent Examiner, Art Unit 1671
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