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 .
Claim Status
Applicant’s amendments and remarks, filed 06/09/2026, are acknowledged.
Claims 3-9, 17-18, 20-21, 23, 25-34, 36-37, 39-51, 54-58, and 60-64 are canceled.
Claim 2 is amended.
Claims 1-2, 10-16, 19, 22, 24, 35, 38, 52-53, 59, and 65-73 are pending.
Claims 52 and 53 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 01/12/2024.
As such, claims 1-2, 10-16, 19, 22, 24, 35, 38, 59, and 65-73 are pending examination and currently under consideration for patentability under 37 CFR 1.104.
DETAILED ACTION
Withdrawn Objections
The claim objections are withdrawn. Issues regarding minor informalities have been sufficiently addressed through amendments to the claims filed on 06/09/2026.
Maintained Rejection(s)
Claim Rejections - 35 USC § 112(a) – Written Description
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-2, 10-16, 19, 22, 24, 35, 38, 59, and 65-72 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 MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.”
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, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, 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 Applicants were in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
Claim 1 is drawn to a chimeric antigen receptor comprising: (a) a means for recognizing a dysfunctional P2X purinoceptor 7 (P2X7) receptor; (b) a transmembrane domain; (c) a linker domain consisting of 70 to 180 amino acids; and (d) a signaling domain comprising an intracellular signaling portion of an activation receptor and an intracellular signaling portion of a co-stimulatory receptor; wherein the dysfunctional P2X7 receptor comprises a proline at amino acid position 210, and wherein the proline has changed from a trans-conformation to a cis-conformation.
Claim 2 is drawn to the chimeric antigen receptor according to claim 1, wherein the linker domain consists of between 90 to 160 amino acids.
Claim 10 is drawn to the chimeric antigen receptor according to claim 1, wherein the linker domain comprises an immunoglobulin hinge region, or a functional variant thereof.
Claim 11 is drawn to the chimeric antigen receptor according to claim 1, wherein the linker domain comprises an immunoglobulin hinge region of IgG, IgD, IgA, or a constant heavy (CH) 2 region of IgM or IgE, or a functional variant thereof.
Claim 12 is drawn to the chimeric antigen receptor according to claim 1, wherein the linker domain comprises a hinge region from an IgG isotype immunoglobulin, or a functional variant thereof.
Claim 13 is drawn to the chimeric antigen receptor according to claim 1, wherein the linker domain comprises a hinge region of an IgG1, IgG2 or IgG4 subclass of immunoglobulin.
Claim 14 is drawn to the chimeric antigen receptor according to claim 1, wherein the linker domain comprises a CXXC motif.
Claim 15 is drawn to the chimeric antigen receptor according to claim 14, wherein the sequence of the CXXC motif is selected from the group of SEQ ID NO: 71, SEQ ID NO: 72, and SEQ ID NO: 73.
Claim 16 is drawn to the chimeric antigen receptor according to claim 1, wherein the linker domain comprises a constant heavy (CH) region of an immunoglobulin.
Claim 19 is drawn to the chimeric antigen receptor according to claim 1, wherein the linker domain consists of one or more immunoglobulin hinge region(s), or one or more CH region(s) of an immunoglobulin.
Claim 22 is drawn to the chimeric antigen receptor according to claim 1, wherein the linker domain comprises an amino acid sequence according to any one of SEQ ID NOs: 11 and 16-17, or comprises a sequence at least 80% identical to any one of SEQ ID Nos: 11 and 16-17.
Claim 24 is drawn to the chimeric antigen receptor according to claim 1, wherein the chimeric antigen receptor does not comprise an amino acid sequence in the linker domain that binds to an Fc receptor.
Claim 35 is drawn to the chimeric antigen receptor according to claim 1, wherein the transmembrane domain comprises all or part of the transmembrane domain of CD8 or CD28.
Claim 38 is drawn to an isolated cell comprising the chimeric antigen receptor according to claim 1.
Claim 59 is drawn to a pharmaceutical composition comprising a genetically modified cell comprising a chimeric antigen receptor according to claim 1, and a pharmaceutically acceptable carrier or excipient.
Claim 65 is drawn to the chimeric antigen receptor according to claim 1, wherein the linker domain consists of 110 to 130 amino acids.
Claim 66 is drawn to the chimeric antigen receptor according to claim 1, wherein the linker domain consists of 115 to 125 amino acids.
Claim 67 is drawn to the chimeric antigen receptor according to claim 1, wherein the linker domain consists of 117 to 121 amino acids.
Claim 68 is drawn to the chimeric antigen receptor according to claim 16, wherein the linker domain comprises one or more types of CH regions selected from a CH1 region, a CH2 region, a CH3 region, and a CH4 region of an immunoglobulin.
Claim 69 is drawn to the chimeric antigen receptor according to claim 68, wherein the linker domain comprises a CH2 region and/or a CH3 region of an IgG isotype immunoglobulin.
Claim 70 is drawn to the chimeric antigen receptor according to claim 19, wherein the linker domain consists of an IgG hinge region or one or more CH region(s) of an immunoglobulin.
Claim 71 is drawn to the chimeric antigen receptor according to claim 70, wherein the linker domain consists of an IgG hinge region or a CH2 or CH3 region of an immunoglobulin.
Claim 72 is drawn to an isolated cell comprising a nucleic acid encoding the chimeric antigen receptor according to claim 1.
The specification discloses chimeric antigen receptor (CAR) constructs comprising: (i) an ectodomain comprising a CSF2RA (human colony stimulating factor 2 receptor alpha) leader sequence, antigen binding domain directed against dysfunctional P2X7 receptors having a trans-conformation to cis-conformational change to the proline at amino acid position 210 (having sequence homology to VH portion of an antibody), (ii) a CD28 transmembrane domain, and (iii) an endodomain comprising the intracellular portion of 41BB, the intracellular portion of the CD3-zeta chain, a T2A self-cleavage site, and a truncated from of the EGFR receptor (EGFRt) that lacks an intracellular signaling domain (the surface expression of EGFRt can be used as a proxy to measure transduction efficiency) (see [0218]; Fig. 1). The ectodomain and the transmembrane domain were linked by one of three linked domains being: a. a linker region of 12 amino acids, comprising a mutated version of the IgG4 hinge region (see Figure 2 and SEQ ID NO: 13 and 38) – generating a CAR referred to as CNA1002. The amino acid sequence and nucleic acid sequence for this CAR is provided by SEQ ID NOs: 54 and 55, respectively; b. a linker region of 119 amino acids, comprising a mutated version of the IgG4 hinge region and the IgG4 CH2 region (see SEQ ID NO: 39) – generating a CAR referred to as CNA1003. The amino acid sequence and nucleic acid sequence for this CAR is provided by SEQ ID NO: 51 and 53, respectively; and c. a linker region of 228 amino acids, comprising a mutated version of the IgG4 hinge region, the IgG4 CH2 region and the IgG4 CH3 region (see SEQ ID NO: 40) – generating a CAR referred to as CNA1004. The amino acid sequence and nucleic acid sequence for this CAR is provided by SEQ ID NO: 56 and 57, respectively (see [0219]).
Additionally, para. [0221] disclose a further family of CARs were constructed (SEQ ID NO: 60 and SEQ ID NO: 61) were prepared comprising a CD8a signaling peptide, an anti-dysfunctional P2X7 binding peptide (referred to as PEP2-2-3) distinct from binding peptide used in the CNA family described above, a transmembrane region comprising a portion of CD28, which also provided a portion of the endodomain, and an intracellular portion comprising an intracellular portion of OX40 and an intracellular portion of the CD3 zeta chain, and a T2A self-cleavage site. The binding peptide and the transmembrane region were linked by a linking domain of 30 amino acids (SEQ ID NO: 41) or 228 amino acids (SEQ ID NO: 63). The 30 amino acid linker domain, comprised a mutated version of the IgG4 hinge region (12 a.a.) proceeded by the linker (G4S)3 (15 a.a.) and followed by the amino acid sequence “DPK” (referred to as BLIV CAR short hinge linker – see SEQ ID NO: 41).
Additionally, the specification discloses of six different CAR constructs comprising different antigen-recognition domains that bind the dysfunctional (specifically, non-functional (nf)) P2X7 receptors wherein three of the CAR constructs comprise antigen-recognition domains (single domain antibodies or sdAb) consisting of peptide binders (CNA1003, CNA1103, CNA1203), two comprised antigen-recognition domains consisting of single variable chains (scFv) from a monoclonal antibody that recognizes nfP2X7 (CNA1303 and CNA1403) and one was a di-peptide (CNA1503) (see [0299]). CNA1003, CNA1103, and CNA1203 were formed of the 3 CDRs from the variable heavy chain of antibodies specific for nfP2X7; CNA1303 and CNA1403 were formed of variable heavy chains from an antibody specific for nfP2X7 coupled, via an amino acid having the sequence set forth in SEQ ID NO: 69, to the variable light chains of distinct anti-nfP2X7 antibodies; and CNA1503 was formed of two dAb regions coupled by an amino acid having the sequence set forth in SEQ ID NO: 69 (see [0299]). These CAR constructs consists of a human colony stimulating factor 2 receptor alpha (CSF2RA) leader sequence, one of the above described antigen-recognition domain (SEQ ID NO: 4 – CNA1003; SEQ ID NO: 64- CNA1103; SEQ ID NO: 65 – CNA1203; SEQ ID NO: 66 – CNA1303; SEQ ID NO: 67 – CNA1403; and SEQ ID NO: 68 – CNA1503), a linker domain (IgG4 hinge-CH3 – 119 amino acids in length), CD28 transmembrane domain, intracellular signaling domains from 41BB and the CD3 zeta domain, with a terminal self-cleavage peptide T2A, and an EGFRt, that lacks an intracellular signaling domain, was co-expressed from the same transcript via the self-cleavage peptide T2A (see [0301]).
Lastly, the specification recites art directed to antibodies that are against dysfunctional P2X7 receptors (see [0106]).
However, the specification fails to disclose that Applicant was in possession of the large genera of claimed CARs. Specifically, the specification and claims fail to define what the “equivalents thereof” are of the species of CARs and antibodies recited in the specification.
Although the specification discloses the following species of CARs: CNA1003, CNA1002, CNA1004, CNA1103, CNA1203, CNA1303, CNA1403, and CNA1503, the claims are not limited to these CARs, and are inclusive of any CAR capable of recognizing a dysfunctional P2X7 receptor, a transmembrane domain and a linker domain, wherein the linker domain consists of between 70 to 180 amino acids. This indicates that there are thousands, of possible CARs encompassed by the claims. The genus is particularly broad because even the target protein is inadequately described; the specification does not even limit the possible target P2X7 receptors, and only describes them as “dysfunctional” without defining structures and correlating dysfunctional characteristics. Thus, the claims encompass a vast genus of CARs, and their individual corresponding components, that have specific, required functions according to the instant claims. However, the specification provides limited guidance on the structure that correlates to the claimed function(s). Therefore, the specification does not provide adequate written description to identify the broad and variable genus of CARs because, inter alia, the specification does not disclose a correlation between the necessary structure of the CARs and the function(s) recited in the claims; and thus, the specification does not distinguish the claimed genus from others, except by function. Although the term antigen receptor does impart some structure, the structure that is common to antigen receptors is generally unrelated to its specific binding function; therefore, correlation is less likely for antigen receptors than for other molecules. Accordingly, the specification does not define any structural features commonly possessed by the members of the genus, because while the description of an ability of the claimed substance may generically describe the molecule’s function, it does not describe the substance itself. While the dependent claims recite that the claim CARs comprises CDR from the heavy chain of antibody (see claim 73), the claims recite a partial structure (i.e., general description of the heavy chain CDRs but no recitation of the light chain CDRs) that must also possess this function. A definition by function does not suffice to define the genus because it is only an indication of what the substance does, rather than what it is; therefore, it is only a definition of a useful result rather than a definition of what achieves the result. In addition, because the genus of substances is highly variable (i.e. each substance would necessarily have a unique structure, See MPEP 2434), the generic description of the substance is insufficient to describe the genus. Further, given the highly diverse nature of CARs, particularly in CDRs, even one of skill in the art cannot envision the structure of a CAR by only knowing its binding characteristics. Thus, the specification does not provide substantive evidence for possession of this large and variable genus, encompassing a potentially massive number of CARs and variants thereof claimed only be a functional characteristic(s) and/or partial structure.
A biomolecule sequence described only by a functional characteristic, without any known or disclosed correlation between that function and the structure of the sequence, normally is not sufficient identifying characteristics for written description purposes, even when accompanied by a method of obtaining the agent. The specification does not adequately describe the correlation between the chemical structure and function of the genus, such as structural domains or motifs that are essential and distinguish members of the genus from those excluded. Thus, the genus of antibodies has no correlation between their structure and function.
MPEP § 2163.03(V) states:
While there is a presumption that an adequate written description of the claimed invention is present in the specification as filed, In re Wertheim, 541 F.2d 257, 262, 191 USPQ 90, 96 (CCPA 1976), a question as to whether a specification provides an adequate written description may arise in the context of an original claim. An original claim may lack written description support when (1) the claim defines the invention in functional language specifying a desired result but the disclosure fails to sufficiently identify how the function is performed or the result is achieved or (2) a broad genus claim is presented but the disclosure only describes a narrow species with no evidence that the genus is contemplated. See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1349-50 (Fed. Cir. 2010) (en banc). The written description requirement is not necessarily met when the claim language appears in ipsis verbis in the specification. “Even if a claim is supported by the specification, the language of the specification, to the extent possible, must describe the claimed invention so that one skilled in the art can recognize what is claimed. The appearance of mere indistinct words in a specification or a claim, even an original claim, does not necessarily satisfy that requirement. “Enzo Biochem, Inc. v. Gen-Probe, Inc., 323 F.3d 956, 968, 63 USPQ2d 1609, 1616 (Fed. Cir. 2002).
Applicant has not shown possession of a representative number of species of CARs comprising a means for recognizing a dysfunctional P2X7 receptor, a transmembrane domain, a linker domain consisting of 70 to 180 amino acids, and a signaling domain; specifically, there is inadequate description of the “equivalents thereof” of the means for recognizing a dysfunctional P2X7 receptor encompassed by the claims. The disclosure of only a few species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure “indicates that the patentee has invented species sufficient to constitute the gen[us].” See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) (“[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.”) (MPEP 2163).
The instant claims do not fully describe the required structure of the CAR capable of recognizing a dysfunctional P2X7 receptor, the transmembrane domain, the linker domain, or signaling domain of the CAR to carry out their functions; specifically, there is inadequate description of the equivalents thereof of the means for recognizing a dysfunctional P2X7 receptor encompassed by the claims. Accordingly, the specification also does not provide adequate written description to identify the broad genus of CARs capable of recognizing a dysfunctional P2X7 receptor, the transmembrane domain, or the linker domain of the CARs, claimed only be a function characteristic(s) and not structures per se, because inter alia, it does not describe a sufficient number and/or a sufficient variety of representative species to reflect the breadth and variation within the claimed genus. Consequently, based on the lack of information within the specification, there is evidence that a representative number and a representative variety of the CARs had not yet been identified and thus, the specification represents little more than a wish for possession. Therefore, one of skill in the art would not conclude that Applicant was in possession of the broad and highly variable genus of CARs claimed only by a partial structure and functional characteristic(s). Thus the method described by the instant specification encompasses an overly broad genus, and there is no correlation between the structure of the CARs and the functional outcome.
In Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017), relying upon Ariad Pharms., Inc. v. Eli Lily & Co., 94 USPQ2d 1161 (Fed Cir. 2010), it is noted that to show invention, a patentee must convey in its disclosure that is “had possession of the claimed subject matter as of the filing date. Demonstrating possession “requires a precise definition” of the invention. To provide this precise definition” for a claim to a genus, a patentee must disclose “a representative number of species within the scope of the genus of structural features common to the members of the genus so that one of skill in the art can visualize or recognize the member of the genus” (see Amgen at page 1358). Also, it is not enough for the specification to show how to make and use the invention, i.e., to enable it (see Amgen at page 1361). An adequate written description must contain enough information about the actual makeup of the claimed products — “a precise definition, such as structure, formula, chemic name, physical properties of other properties, of species falling with the genus sufficient to distinguish the gene from other materials”, which may be present in “functional terminology when the art has established a correlation between structure and function” (Amgen page 1361). Most significant to the present case, the Court held that “knowledge of the chemical structure of an antigen [does not give] the required kind of structure-identifying information about the corresponding antibodies” (Amgen at 1361). The idea that written description of an antibody can be satisfied by the disclosure of a newly-characterized antigen “flouts basic legal principles of the written description requirement” as it “allows patentees to claim antibodies by describing something that is not the invention, i.e., the antigen... And Congress has not created a special written description requirement for antibodies” (Amgen at page 1362).
Abbvie v. Centocor (Fed. Cir. 2014) is also relevant to the instant claims. In Abbvie, the Court held that a disclosure of many different antibodies was not enough to support the genus of all neutralizing antibodies because the disclosed antibodies were very closely related to each other in structure and were not representative of the full diversity of the genus. The Court further noted that functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support especially in technology fields that are highly unpredictable where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus.
The instant case has many similarities to AbbVie above. First, the claims clearly attempt to define the genus of CARs by the functions of recognizing a dysfunctional P2X7 receptor; specifically, there is inadequate description of the equivalents thereof of the means for recognizing a dysfunctional P2X7 receptor encompassed by the claims. As noted by AbbVie above, functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description. Second, there is no information in the specification based upon which one of skill in the art would conclude that the disclosed species for which applicant has identified as having the recited functions would be representative of the entire genus. The specification discloses no structure to correlate with the function. Therefore, the specification provides insufficient written description to support the genus encompassed by the claim.
Furthermore, regardless whether a compound is claimed per se or a method is claimed that entails the use of the compound, the inventor cannot lay claim to that subject matter unless he can provide a description of the compound sufficient to distinguish infringing compounds from non-infringing compounds, or infringing methods from non-infringing methods. Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920-23, 69 USPQ2d 1886, 1890-93 (Fed. Cir. 2004).
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116.)
Further, the skilled artisan cannot envision the detailed chemical structure of the encompassed CARs, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. The nucleic acid and/or protein itself is required. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. In Fiddes v. Baird, 30 USPQ2d 1481, 1483, claims directed to mammalian FGF’s were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
Finally, University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404. 1405 held that: ... To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that “the inventor invented the claimed invention.” Lockwood v. American Airlines Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (“ [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed.”). Thus, an applicant complies with the written description requirement “by describing the invention, with all its claimed limitations, not that which makes it obvious,” and by using “such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention.” Lockwood, 107 F.3d at 1572, 41 USPQ2d 1966.
Regarding the encompassed antigen-recognition domain, the functional characteristics of these domains (including binding specificity and affinity) are dictated on their structure. Amino acid sequence and conformation of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin. For example, Vajdos et al. (J Mol Biol. 2002 Jul 5;320(2):415-28 at 416; previously submitted with the action mailed 04/11/2024) teaches that, “ … Even within the Fv, antigen binding is primarily mediated by the complementarity determining regions (CDRs), six hypervariable loops (three each in the heavy and light chains) which together present a large contiguous surface for potential antigen binding. Aside from the CDRs, the Fv also contains more highly conserved framework segments which connect the CDRs and are mainly involved in supporting the CDR loop conformations, although in some cases, framework residues also contact antigen. As an important step to understanding how a particular antibody functions, it would be very useful to assess the contributions of each CDR side-chain to antigen binding, and in so doing, to produce a functional map of the antigen-binding site.” The art shows an unpredictable effect when making single versus multiple changes to any given CDR. For example, Brown et al. (J Immunol. 1996 May;156(9):3285-91 at 3290 and Tables 1 and 2; previously submitted with the action mailed 04/11/2024), describes how the VH CDR2 of a particular antibody was generally tolerant of single amino acid changes, however the antibody lost binding upon introduction of two amino changes in the same region.
The claims encompass an extremely large number of possible CARs that are capable to “recognize a dysfunctional P2X7 receptor” that have specific required functions. In the instant application, neither the art nor the specification provide a sufficient representative number of CARs or a sufficient structure-function correlation to meet the written description requirements.
In Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017), relying upon Ariad Pharms., Inc. v. Eli Lily & Co., 94 USPQ2d 1161 (Fed Cir. 2010), it is noted that to show invention, a patentee must convey in its disclosure that is “had possession of the claimed subject matter as of the filing date. Demonstrating possession “requires a precise definition” of the invention. To provide this precise definition” for a claim to a genus, a patentee must disclose “a representative number of species within the scope of the genus of structural features common to the members of the genus so that one of skill in the art can visualize or recognize the member of the genus” (see Amgen at page 1358). Also, it is not enough for the specification to show how to make and use the invention, i.e., to enable it (see Amgen at page 1361). An adequate written description must contain enough information about the actual makeup of the claimed products — “a precise definition, such as structure, formula, chemic name, physical properties of other properties, of species falling with the genus sufficient to distinguish the gene from other materials”, which may be present in “functional terminology when the art has established a correlation between structure and function” (Amgen page 1361). Most significant to the present case, the Court held that “knowledge of the chemical structure of an antigen [does not give] the required kind of structure-identifying information about the corresponding antibodies” (Amgen at 1361). The idea that written description of an antibody can be satisfied by the disclosure of a newly-characterized antigen “flouts basic legal principles of the written description requirement” as it “allows patentees to claim antibodies by describing something that is not the invention, i.e., the antigen... And Congress has not created a special written description requirement for antibodies” (Amgen at page 1362).
Abbvie v. Centocor (Fed. Cir. 2014) is also relevant to the instant claims. In Abbvie, the Court held that a disclosure of many different antibodies (in that case neutralizing antibodies to IL-12 with a particular binding affinity) was not enough to support the genus of all IL-12 neutralizing antibodies because the disclosed antibodies were very closely related to each other in structure and were not representative of the full diversity of the genus. The Court further noted that functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support especially in technology fields that are highly unpredictable where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus.
The instant case has many similarities to Abbvie above. First, the claims clearly attempt to define the genus of CARs. As noted by Abbvie above, functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description. Second, there is no description of any specific embodiments of the “equivalents thereof”, based upon which one of skill in the art would conclude that applicant has identified a representative number of species that have the recited functions.
Furthermore, regardless whether a compound is claimed per se or a method is claimed that entails the use of the compound, the inventor cannot lay claim to that subject matter unless he can provide a description of the compound sufficient to distinguish infringing compounds from non-infringing compounds, or infringing methods from non-infringing methods. Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920-23, 69 USPQ2d 1886, 1890-93 (Fed. Cir. 2004).
Regarding the encompassed proteins and peptides, protein chemistry is one of the most unpredictable areas of biotechnology. This unpredictability prevents prediction of the effects that a given number or location of mutation will have on a protein (such as TNF or a cytokine) as taught by Skolnick et al. (Trends Biotechnol. 2000 Jan;18(1):34-9; previously submitted with the action mailed 04/11/2024), sequence-based methods for predicting protein function are inadequate because of the multifunctional nature of proteins (see e.g. abstract). Further, just knowing the structure of the protein is also insufficient for prediction of functional sites (see e.g. abstract). Sequence to function methods cannot specifically identify complexities for proteins, such as gain and loss of function during evolution, or multiple functions possible within a cell (see e.g. page 34, right column). Skolnick advocates determining the structure of the protein, then identifying the functionally important residues since using the chemical structure to identify functional sites is more in line with how a protein actually works (see e.g. page 34, right column).
The sensitivity of proteins to alterations of even a single amino acid in a sequence are exemplified by Burgess et al. (J. Cell Biol. 111:2129-2138, 1990; previously submitted with the action mailed 04/11/2024) 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 and by Lazar et al. (Mol. Cell. Biol., 8:1247-1252, 1988; previously submitted with the action mailed 04/11/2024) who teach that in transforming growth factor alpha, replacement of aspartic acid at position 47 with alanine or asparagine did not affect biological activity while replacement with serine or glutamic acid sharply reduced the biological activity of the mitogen. These references demonstrate that even a single amino acid substitution will often dramatically affect the biological activity and characteristics of a protein.
Further, Miosge (Proc Natl Acad Sci U S A. 2015 Sep 15;112(37):E5189-98; previously submitted with the action mailed 04/11/2024) teach that short of mutational studies of all possible amino acid substitutions for a protein, coupled with comprehensive functional assays, the sheer number and diversity of missense mutations that are possible for proteins means that their functional importance must presently be addressed primarily by computational inference (see e.g. page E5189, left column). However, in a study examining some of these methods, Miosge shows that there is potential for incorrect calling of mutations (see e.g. page E5196, left column, top paragraph). The authors conclude that the discordance between predicted and actual effect of missense mutations creates the potential for many false conclusions in clinical settings where sequencing is performed to detect disease-causing mutations (see e.g. page E5195, right column, last paragraph). The findings in their study show underscore the importance of interpreting variation by direct experimental measurement of the consequences of a candidate mutation, using as sensitive and specific an assay as possible (see e.g. page E5197, left column, top paragraph). Additionally, Bork (Genome Research, 2000,10:398-400; previously submitted with the action mailed 04/11/2024) clearly teaches the pitfalls associated with comparative sequence analysis for predicting protein function because of the known error margins for high-throughput computational methods. Bork specifically teaches that computational sequence analysis is far from perfect, despite the fact that sequencing itself is highly automated and accurate (p. 398, column 1). One of the reasons for the inaccuracy is that the quality of data in public sequence databases is still insufficient. This is particularly true for data on protein function. Protein function is context dependent, and both molecular and cellular aspects have to be considered (p. 398, column 2). Conclusions from the comparison analysis are often stretched with regard to protein products (p. 398, column 3). Further, although gene annotation via sequence database searches is already a routine job, even here the error rate is considerable (p. 399, column 2). Most features predicted with an accuracy of greater than 70% are of structural nature and, at best, only indirectly imply a certain functionality (see legend for table 1, page 399). As more sequences are added and as errors accumulate and propagate it becomes more difficult to infer correct function from the many possibilities revealed by database search (p. 399, paragraph bridging columns 2 and 3). The reference finally cautions that although the current methods seem to capture important features and explain general trends, 30% of those features are missing or predicted wrongly. This has to be kept in mind when processing the results further (p. 400, paragraph bridging cols 1 and 2).
One key issue is the prediction of protein function based on sequence similarity, which could be one way to identify the functional proteins that are useful in the instant claims. Kulmanov et al (Bioinformatics, 34(4), 2018, 660–668; previously submitted with the action mailed 04/11/2024), teach that there are key challenges for protein function prediction methods (see e.g. page 661, left column). These challenges arise from the difficulty identifying and accounting for the complex relationship between protein sequence structure and function (see e.g. page 661, left column). Despite significant progress in the past years in protein structure prediction, it still requires large efforts to predict protein structure with sufficient quality to be useful in function prediction (see e.g. page 661, left column). Another challenge is that proteins do not function in isolation. In particular higher level physiological functions that go beyond simple molecular interactions will require other proteins and cannot usually be predicted by considering a single protein in isolation (see e.g. page 661, left column). Due to these challenges it is not obvious what kinds of features should be used to predict the functions of a protein and whether they can be generated efficiently for a large number of proteins, such as the vast genus of proteins and peptides that may be encompassed by the instant claims (see e.g. page 661, left column).
The state of the art regarding the structure-function correlation cannot be relied upon because functional characteristics of any peptide/protein are determined by its structure as evidenced by Greenspan et al. 1999 (Defining epitopes: It’s not as easy as it seems; Nature Biotechnology, 17:936-937; previously submitted with the action mailed 04/11/2024). Greenspan et al. teach that as little as one substitution of an amino acid (e.g. alanine) in a sequence results in unpredictable changes in the 3-dimenstional structure of the new peptide sequence which, in turn, results in changes in the functional activity such as binding affinity of the peptide sequence (page 936, 1st column). Greenspan et al. teach that contribution of each residue (i.e. each amino acid) cannot be estimated with any confidence if the replacement affects the properties of the free form of the molecule (page 936, 3rd column).
Given not only the teachings of Skolnick et al., Lazar et al., Burgess et al., and Greenspan et al., but also the limitations and pitfalls of using computational sequence analysis and the unknown effects of alternative splicing, post translational modification and cellular context on protein function as taught by Bork, the claimed CARs could not be predicted based on sequence identity. Clearly, it could not be predicted that a polypeptide or a variant that shares only partial homology with a disclosed protein or that is a fragment of a given SEQ ID NO. will function in a given manner.
The claimed invention as a whole may not be adequately described where an invention is described solely in terms of a method of its making coupled with its function and there is no described or art-recognized correlation or relationship between the structure of the invention and its function (see MPEP 2163). A patent specification must set forth enough detail to allow a person of ordinary skill in the art to understand what is claimed and to recognize that the inventor invented what is claimed. In the case of DNA, an adequate written description requires a precise definition, such as by structure, formula, chemical name, or physical properties, not a mere wish or plan for obtaining the claimed chemical invention (see Lilly, 119 F.3d at 1566 (quoting Fiers, 984 F.2d 15 1171 ). Because the specification does not describe the amino acid sequences nor any core structures for potentially numerous different antibody amino acid sequences which would have the recited dissociation constant, one of skill in the art would reasonably conclude that applicant was not in possession of the claimed genus of all CARs that recognize dysfunctional P2X7 receptors.
Recently, the U.S. Court of Appeals for the Federal Circuit (Federal Circuit) decided Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017), which concerned adequate written description for claims drawn to antibodies. The Federal Circuit explained in Amgen that when an antibody is claimed, 35 U.S.C. § 112(a) requires adequate written description of the antibody itself even when preparation of such an antibody would be routine and conventional. Amgen, 872 F.3d at 1378-79. A key role played by the written description requirement is to prevent “attempt[s] to preempt the future before it has arrived.” Ariad at 1353, (quoting Fiers v. Revel, 984 F.2d at 1171). Upholding a patent drawn to a genus of antibodies that includes members not previously characterized or described could negatively impact the future development of species within the claimed genus of antibodies.
Lastly, Applicants have not shown possession of a representative number of species CARs. As noted above, the claims are generic for the components of the CAR. Applicant has not demonstrated possession of CARs. The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure “indicates that the patentee has invented species sufficient to constitute the gen[us].” See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) (“[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.”) (MPEP 2163).
Regarding the means-plus-function language, the MPEP 2181(I) states: “A claim limitation is presumed to invoke 35 U.S.C. 112(f) when it explicitly uses the term "means" or "step" and includes functional language. The presumption that 35 U.S.C. 112(f) applies is overcome when the limitation further includes the structure, material or acts necessary to perform the recited function. See TriMed, Inc. v. Stryker Corp., 514 F.3d 1256, 1259-60, 85 USPQ2d 1787, 1789 (Fed. Cir. 2008) ("Sufficient structure exists when the claim language specifies the exact structure that performs the function in question without need to resort to other portions of the specification or extrinsic evidence for an adequate understanding of the structure."); see also Altiris, Inc. v. Symantec Corp., 318 F.3d 1363, 1376, 65 USPQ2d 1865, 1874 (Fed. Cir. 2003).” The amendment to add “means for” language further fails to comply with the written description requirement because Applicant fails to adequately describe the “equivalents thereof” of the CAR (i.e., the means for recognizing a dysfunctional P2X7 receptor) to perform the required functions. The specification states “A chimeric antigen receptor, which targets cells expressing a dysfunctional P2X7 receptor, is described in the international publication WO2017/041143, the entire disclosure of which is incorporated by way of this reference” (see [0084]). The embodiments listed in the specification limit the CARs to specific structures; while some structures are named, some have no structure described. The specification states that “CARs are artificially constructed proteins that upon expression on the surface of a cell can induce an antigen-specific cellular response. A CAR includes at a minimum three domains; the first domain being an extracellular antigen-recognition domain that specifically recognizes an antigen, or more specifically an epitope portion, or portions, of an antigen; the second domain being an intracellular signaling domain that is capable of inducing, or participating in the induction, of an intracellular signaling pathway; and the third being a transmembrane domain that traverses the plasma membrane and bridges the extracellular antigen-recognition domain and the intracellular signaling domain” (see [0075]). None of these statements require any specific structure, or any specific linker. Applicant has neither defined the “means” by which binding should occur under the required interpretation under 35 USC 112(f), nor provided adequate written description for the encompassed embodiments. While there are a limited number of CARs defined by sequence structures, the terms for the CARs and/or components within the CAR do not limit the claimed molecule to these structures. Given the broadest reasonable interpretation, the only functional and structural requirements are those that are already recited in the claims, which do not adequately describe the genus of encompassed CARs. While Table 1 recites several species of CARs against dysfunctional P2X7 receptors, this table does not meet the requirements of means-plus function because it is unclear, based on the facts of the application, that one skilled in the art would have known what the “equivalents thereof” are in reference to the species recited in the specification. For example, it is unclear if the “equivalents thereof” are solely different sequences of the recognition domain of the CAR described in the specification, or different recognition domains all together.
While “examples explicitly covering the full scope of the claim language” typically will not be required, a sufficient number of representative species must be included to “demonstrate that the patentee possessed the full scope of the [claimed] invention.” Lizard tech v. Earth Resource Mapping, Inc., 424 F.3d 1336, 1345, 76 USPQ2d 1724,1732 (Fed. Cir. 2005).
In the absence of sufficient recitation of distinguishing characteristics, the specification does not provide adequate written description of the claimed genus. One of skill in the art would not recognize from the disclosure that the applicant was in possession of the claimed CARs. Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features (see, Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916,927, 69 USPQ2d 1886, 1895 (Fed. Cir. 2004); accord Ex Parte Kubin, 2007-0819, BPAI 31 May 2007, opinion at p. 16, paragraph 1). The specification does not clearly allow persons of ordinary skill in the art to recognize that he or she invented what is claimed (see Vas-Cath at page 1116).
Without an adequate description of the “equivalents thereof”, one of ordinary skill in the art would not be reasonably apprised that Applicant was in possession of the genus of CARs as claimed. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. 112 is severable from its enablement provision (see page 1115).
Applicant’s Arguments
Applicant respectfully disagrees with the written description rejection (see pages 8-11 of the Remarks filed on 06/09/2026). First, Applicant has amended the specification to delete paragraph [0106]. With this amendment, the specification does not reference publications describing P2X7 antibodies, and the scope of the corresponding structures disclosed in the specification is limited to the specific CAR constructs set forth in, e.g., Table 1 and Example 4, that have corresponding structures that perform the recited function of recognizing a dysfunctional P2X7 receptor. These species, while having different amino acid sequences, share common structural features: they are all antibody-derived antigen-recognition domains comprising CDRs that specifically bind the dysfunctional P2X7 receptor. Applicant submits that this is analogous to the situation in Ex parte Chamberlain (Appeal 2022-001944), where the specification disclosed a single antibody (5G1.1) that performs the claimed function, and the Board held that the written description requirement was satisfied. Moreover, the fact that the instant specification discloses more corresponding structures than the single antibody in Chamberlain should weigh in favor of adequate written description, not against it. If a single disclosed structure was sufficient to satisfy the written description requirement in Chamberlain, then the multiple fully characterized CAR constructs disclosed in the instant specification should satisfy the requirement.
Response to Arguments
Applicant's arguments filed 06/09/2026 have been fully considered but they are not persuasive. Examiner acknowledges that paragraph [0106] was deleted from the specification. However, paragraphs [0104], [0105], [0160], and [0162] recite the species of Table 1 and Example 4 and variances thereof with at least 50% sequence identity to the species of Table 1 and Example 4. The specification fails to disclose which sequences must be maintained in order to keep their function (i.e., recognizing a dysfunctional P2X7 receptor), thus it is unclear to identify the “equivalents thereof” of the different species disclosed in Table 1 and Example 4. As stated in Applicant’s remarks and in the previous Office Action, Chamberlain was limited to antibody 5G1.1, thus there is sufficient support for equivalents thereof. The facts of Chamberlain can be distinguished from the instant application because the present application encompass the species of Table 1, Example 4, and variants thereof which indicates that there are thousands of possible CARs encompassed by the claims. Thus, it cannot be determined what is encompassed by the “equivalents” doctrine of 112(f).
As such, the written description rejection is maintained.
Allowable Subject Matter
Claim 73 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims. As stated above, Examiner acknowledges that the amendments to claim 73 overcome the written description rejection for this claim. Specifically, examiner acknowledges that claim 73 was amended to specify that the means for recognizing a dysfunctional P2X7 receptor is a single domain antibody.
Conclusion
Claims 1-2, 10-16, 19, 22, 24, 35, 38, 59, and 65-72 are rejected.
Claim 73 is objected to.
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 nonprovisional extension fee (37 CFR 1.17(a)) 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.
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/DANAYA L MIDDLETON/Examiner, Art Unit 1674
/VANESSA L. FORD/Supervisory Patent Examiner, Art Unit 1674
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