Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Detailed Action
This action is in response to the papers filed January 19, 2026.
Amendments
Applicant's response and amendments, filed January 19, 2026, is acknowledged. Applicant has cancelled Claims 2-4, 21, 28, and 30-31, and amended Claims 29 and 32.
Claims 1, 5-20, 22-27, 29, and 32-36 are pending and under examination.
Priority
This application is a 371 of PCT/US2020/064415 filed on December 11, 2020. Applicant’s claim for the benefit of a prior-filed application provisional application 62/951,309 filed on December 20, 2019 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
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.
1. Claim 32 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 32 has been amended to recite the limitation “of claim 30”. There is insufficient antecedent basis for this limitation in the claim because Claim 30 has been cancelled.
Appropriate correction is required.
2. Claims 13, 16, 22, 25, 27, 29, and 32-36 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.
Claims 13, 22, and 29 recite a chimeric antigen receptor (CAR) [structure] that has the functional property of binding to GPC-3, said CAR comprising:
a) a heavy chain variable region comprising the VH CDR1, CDR2, and CDR motifs of SEQ ID NO’s: 37-39, respectively, and
b) a light chain variable region comprising:
i) the VL CDR1, CDR2, and CDR motifs of SEQ ID NO’s: 40-42, respectively; or
ii) the VL CDR1, CDR2, and CDR motifs of SEQ ID NO’s: 43-45, respectively.
In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described by their complete structure. To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. The disclosure of a single species is rarely, if ever, sufficient to describe a broad genus, particularly when the specification fails to describe the features of that genus, even in passing. (see In re Shokal 113USPQ283(CCPA1957); Purdue Pharma L.P. vs Faulding Inc. 56 USPQ2nd 1481 (CAFC 2000).
The court explained that “reading a claim in light of the specification, to thereby interpret limitations explicitly recited in the claim, is a quite different thing from ‘reading limitations of the specification into a claim,’ to thereby narrow the scope of the claim by implicitly adding disclosed limitations which have no express basis in the claim.” The court found that applicant was advocating the latter, i.e., the impermissible importation of subject matter from the specification into the claim.). See also In re Morris, 127 F.3d 1048, 1054-55, 44 USPQ2d 1023, 1027-28 (Fed. Cir. 1997).
Claims 14-15 recite scFv VH and VL amino acid sequences of SEQ ID NO’s 27-30, whereby the scFv VH domain is 116 amino acids and the scFv VL domain is 110 amino acids.
The claim is directed to an enormously vast genus of structurally undisclosed chimeric antigen receptor molecules ranging from 314 to 501 amino acids in length that are to have the functional properties of binding to GPC-3, whereby said genus of CARs may have a genus of different binding affinity Kd functional properties, to wit, 100nM, 75nM, 100pM, 25pM, 750fM, 250fM, 100fM, or 1fM, etc…
20^116 = about 8x10^150 structurally and functionally undisclosed scFv VH domain polypeptides that are to have the functional property of binding GPC3.
20^110 = about 8x10^143 structurally and functionally undisclosed scFv VH domain polypeptides that are to have the functional property of binding GPC3.
(www.calculator.net/exponent-calculator; of record; last visited January 27, 2026)
The claims encompass a genus of structurally unrecited and undisclosed additional elements of the chimeric antigen receptor, e.g. a transmembrane domain, a costimulatory domain, and a signal domain, as recited at a high level of generality in Claims 16 and 25.
Claim 26 recites CAR construct amino acid SEQ ID NO’s: 3-10 and 25, which vary in lengths of 314, 318, 455, 456, 459, 460, 497, and 501 amino acids.
Thus, the independent claims reasonably encompass chimeric antigen receptors comprising:
about 8x10^150 structurally and functionally undisclosed scFv VH domain polypeptides of 116 amino acids that are to have the functional property of binding GPC3;
about 8x10^143 structurally and functionally undisclosed scFv VH domain polypeptides of 110 amino acids that are to have the functional property of binding GPC3; and
an infinite (501-226 = 275; 20^275 = infinite) and/or enormously vast genus of about 3x10^304 and/or 4x10^119 (460-226 = 234; 20^234 = 3x10^304; 318-226 = 92; 20^92 = 4x10^119) structurally and functionally undisclosed additional elements of the chimeric antigen receptor, e.g. the transmembrane domain, the costimulatory domain(s), and the signal domain(s), and combinations and/or subcombinations thereof.
Without a correlation between structure and function, the claim does little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (“definition by function ... does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is’).
Given the highly diverse structural nature of antibodies, particularly in the CDRs, one of ordinary skill in the art generally cannot envision the structure of an antibody by knowing its binding characteristics.
It is well established in the art that the formation of an intact antigen-binding site generally requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs or hypervariable regions 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 a given antibody. It is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences, which maintain the required conformation of the CDRs are required in order to produce a protein having antigen-binding function; and further, that proper association of heavy and light chain variable regions is required in order to form functional binding sites.
MacCallum et al (Antibody-antigen Interactions: Contact Analysis and Binding Site Topography, J. Mol. Biol. 262:732-745, 1996) analyzed many different antibodies for interactions with antigen and state that although CDR3 of the heavy and light chain dominate, a number of residues outside the standard CDR definitions make antigen contacts (pg 733, col. 2) and non-contacting residues within the CDRs coincide with residues as important in defining canonical backbone conformations (pg 735, col. 1).
The fact that not just one CDR is essential for antigen binding or maintaining the conformation of the antigen binding site, is underscored by Casset et al (A peptide mimetic of an anti-CD4 monoclonal antibody by rational design, Biochem. Biophys. Res. Comm. 307:198-205, 2003), who constructed a peptide mimetic of an anti-CD4 monoclonal antibody binding site by rational design and the peptide was designed with 27 residues formed by residues from 5 CDRs (see entire document). Casset et al also states that although CDR H3 is at the center of most if not all antigen interactions, clearly other CDRs play an important role in the recognition process (pg 199, col. 1). Thus, while one can make the statement that CDRs from a single antibody chain make a significant contribution in the antigen binding, the CDR domains from a single chain are not the only residues that influence binding, and in fact the prior art does not support that CDR domains from a single chain alone are sufficient to define the binding specificity of an antibody.
While CDRs are provided, it has been well-documented that both the FRs and CDRs are required for binding, Sela-Culang et al (The structural basis of antibody-antigen recognition, Frontiers in Immunology 4: Article 302, 13 pages, doi: 10.3389/fimmu.2013.00302; available online October 8, 2013) is considered relevant prior art for having taught that while the six CDRs are widely assumed to be responsible for antigen recognition, recent studies and analyses of a growing number of available antibody structures indicate that this assumption is an oversimplification. Some amino acid positions in the CDRs have been shown to never participate in antigen binding, and some amino acid positions in the framework regions, outside the CDRs, often contribute critically to the interaction with antigen (e.g. Abstract).
Rather, some studies indicate that only 20-30% of the CDR residues participate in antigen binding, while the remaining residues are important for maintaining structural conformations of the hypervariable loops (e.g. pg 4, col. 1).
Sela-Culang et al taught that “it is now well established that some of the FR residues may play an important role in Ag binding.” The FR regions can influence antigen binding both directly and indirectly (e.g. pg 7, col. 1).
Sela-Culang et al taught that the prior art recognized that simply grafting only the CDRs of a mouse antibody onto a human variable region framework usually results in a significant drop, or a complete loss, of antigen binding. In order to restore antigen binding, one needs to mutate back some of the framework residues to the original mouse antibody (e.g. pg 7, col. 1).
Some of these framework residues that contact and bind the antigen are close in sequence to the CDRs, while other framework residues are far from the CDRs in the primary sequence, but closer proximity in the 3-D structure (e.g. pg 7, col’s 1-2, joining para).
A second category of framework residues that affect antigen binding are those that affect antigen binding indirectly, e.g.:
i) by providing a structural support to the CDRs, enabling them to adopt the right conformation and orientation, shaping the binding site required for antigen binding; or
ii) maintaining the overall structure of the Fv domains by directing the relative orientation of the VH vs VL domains, and thus the orientation of the CDRs relative to each other (e.g. pg 7, col. 2).
Rudikoff et al (Single Amino Acid Substitution Altering Antigen-binding Specificity, PNAS 79:1979-1983, 1982; of record) taught that a single amino acid substitution is sufficient to alter the antigen-binding specificity, and thus alters antigen-binding affinity constants. While CDR mutation might be expected to alter antigen binding of an antibody, framework mutations can also have an effect.
Panka et al (Variable region framework differences result in decreased or increased affinity of variant anti-digoxin antibodies, Proceedings of the National Academy of Sciences USA, Vol., 85, 1988; of record) taught that a single amino acid difference in a framework residue at the boundary with CDR3 was responsible for the decreased affinity of an anti-digoxin antibody (pg. 3083, col. 1, para 1).
Vu et al (U.S. 2015/0368351; of record) disclosed that the same antigen binding domain will have different binding affinity values, corresponding (Koff) values, and corresponding (Kon) values, depending upon the target antigen (Table 6). Thus, knowing the structure of an antigen binding domain does not immediately lead to knowing the corresponding values of binding affinity and kinetics to the corresponding target antigen. Rather, each of the values must be determined empirically.
Goel et al (Plasticity within the Antigen-Combining Site May Manifest as Molecular Mimicry in the Humoral Immune Response, J. Immunol. 173: 7358-7367, 2004; of record) taught the generation of monoclonal antibodies directed to the same antigen, whereby three antibodies that bind to the same 12-mer epitope/antigen have substantial amino acid diversity in the CDRs (Figure 3) and binding kinetics (Table III, Figure 6).
Poosarla et al (Computational De Novo Design of Antibodies Binding to a Peptide With High Affinity, Biotech. & Bioengin. 114(6): 1331-1342, 2017; of record) designed scFv fragments that bind to the same 12-mer epitope/antigen, and demonstrate substantial diversity in said antibody amino acid sequences (Figure 3). It appears that even though all antibodies bind to the same 12-mer they bind to different epitopes within it.
Edwards et al (The Remarkable Flexibility of the Human Antibody Repertoire; Isolation of Over One Thousand Different Antibodies to a Single Protein, BLyS, J. Mol. Biol. 334: 103-118, 2003; of record) taught the ability to identify over 1000 antibodies composed of structurally different amino acid sequences that bind to a single antigen (see entire paper).
Srivastava and Riddell (Engineering CAR-T cells: Design concepts, Trends Immunol. 36(8): 494-502; available online July 15, 2015; of record) taught that while the biochemical principles of (Kon)/ (Koff) rates, and binding affinity were recognized in the art for being important parameters when designing CARs (Table 2), such values must be determined empirically to optimally activate T cells for tumor recognition (pgs 500-501, joining ¶).
Schier et al (Isolation of Picomolar Affinity Anti-c-erbB-2 Single-chain Fv by Molecular Evolution of the Complementarity Determining Regions in the Center of the Antibody Binding Site, J. Mol. Biol. 263: 551-567, 1996; of record) taught that the binding kinetics of antibody-based antigen binding domains will change with but one amino acid difference as compared to a reference sequence (Tables 2-4).
Brack et al (U.S. Patent 7,968,685; of record) is considered relevant prior art for having disclosed an antibody comprising an amino acid sequence (SEQ ID NO:58, lower line) that is 96% identical to instant SEQ ID NO:27 (upper line), wherein said antibody comprises a CDR1 motif and a CDR2 motif that are identical to the instant CDR1 and CDR2 motifs of SEQ ID NO:27, and wherein the CDR motif is substantially similar (2 conservative changes, 1 non-conservative change) to the CDR3 motif of instant SEQ ID N:27, as shown below:
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGSTYY
||||:|||||||||||||||||||||||||||||||||||||||||||||||||||||||
EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGSTYY
ADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGKRYFDYWGQGTMVTVS
|||||||||||||||||||||||||||||||||||||:|:| ||||||||:||||
ADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKGRRIFDYWGQGTLVTVS
However, the antibody binds Tenascin-C, not GPC3.
Instant SEQ ID NO:29, having the same CDR1 and CDR2 motifs as SEQ ID NO:27, evidences that the conservative substitutions R>K and/or K>R are not dispositive in the CDR3 motif to specify GPC3-binding, rather than Tenascin-C-binding.
SEQ ID NO:27 (upper)/SEQ ID NO:29 (lower) (1aa difference)
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGSTYY
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGSTYY
ADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGKRYFDYWGQGTMVTVSS
|||||||||||||||||||||||||||||||||||||:||||||||||||||||||
ADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKGKRYFDYWGQGTMVTVSS
Walker (U.S. Patent 11,725,045; of record) is considered relevant prior art for having disclosed an antibody directed to respiratory syncytial virus (RSV) antibody whose VL domain (SEQ ID NO:766) whose amino acid sequence is about 93% identical to instant SEQ ID NO:28 (upper line), as shown below:
SYELTQPPSASGTPGQRVTISCSGGSSNIGSNTVNWFRQLPGTAPKLLVYFNNQRPSGVP
|||||||||||||||||||||||| |||||||||||::||||||||||:| |||||||||
SYELTQPPSASGTPGQRVTISCSGSSSNIGSNTVNWYQQLPGTAPKLLIYSNNQRPSGVP
DRFSGSKSGTSASLAIGGLQSDDEADYYCVAWDDSLNAPVFGGGTKVTVL
|||||||||||||||| ||||:||||||| ||||||| ||||||||:|||
DRFSGSKSGTSASLAISGLQSEDEADYYCAAWDDSLNGPVFGGGTKLTVL
Thus, knowing the identity of the target antigen does not inform the artisan as to the amino acid sequence of the corresponding peptide or antibody that can bind to said target antigen.
Moreira et al (Hot spots—A review of the protein–protein interface determinant amino-acid residues, Proteins 68: 803-812, 2007) is considered relevant prior art for having taught Protein–protein interactions are very complex and can be characterized by their size,
shape, and surface complementarity (e.g. pg 803, Protein-Protein). The hydrophobic and electrostatic interactions they establish, as well as the flexibility of the molecules involved, are very significant.
Moreira et al taught that in a protein–protein interface, a small subset of the buried amino acids typically contribute to the majority of binding affinity as determined by the change in the free energy of binding. Although there is no purely geometric reason, these energetic determinants are compact, centralized regions of residues crucial for protein association (e.g. pg 804, col. 2).
Moreira et al taught that most interfaces are optimal tight-fitting regions characterized by complementary pockets scattered through the central region of the interface, and enriched in structurally conserved residues. These pockets are classified as ‘‘complementary’’ because there is a large complementarity both in shape and in the juxtaposition of hydrophobic and hydrophilic hot spots, with buried charged residues forming salt bridges and hydrophobic residues from one surface fitting into small nooks on the opposite face. Usually, the hot spot of one face packs against the hot spot of the other face establishing a region determinant for complex binding (e.g. pg 806, col. 1). Complementarity is basically affected by the size of the buried surface, alignment of polar and nonpolar residues, number of buried waters, and the packing densities of atoms involved in the protein–protein interface. Packing defects at the protein–protein interface result in these gaps or pockets, and it is unclear whether unfilled pockets contain water molecules or how the dynamics of water molecules entering and escaping these pockets may affect binding stability (e.g. pg 807, col. 2). Moreira et al taught that common methodology to determine hot spot locations on the artisan’s protein of interest, alanine-scanning mutagenesis is slow and labor-intensive (e.g. pg 804, col. 1). Similarly, systematic mutagenesis is very laborious and time-consuming to perform, as individual mutant proteins must be purified and analyzed separately (e.g. pg 808, col. 2).
Ng et al (Predicting the Effects of Amino Acid Substitutions on Protein Function, Annual Review Genomics Human Genetics 7: 61-80, 2006) is considered relevant prior art for having taught that non-synonymous nucleotide changes which introduce amino acid changes in the corresponding protein have the largest impact on human health. Most algorithms to predict amino acid substation consequences of protein function indicate about 25% to 30% of amino acid changes negatively affect protein function (Abstract). Existing prediction tools primarily focus on studying the deleterious effects of single amino acid substitutions through examining amino acid conservation at the position of interest among related sequences, an approach that is not directly applicable to multiple amino acid changes, including insertions or deletions. Ng et al taught that 83% of disease-causing mutations affect protein stability (e.g. pg 63, col. 1), which in this case, would affect the ability of the enormously vast genus of about chimeric antigen receptors comprising:
about 8x10^150 structurally and functionally undisclosed scFv VH domain polypeptides of 116 amino acids that are to have the functional property of binding GPC3;
about 8x10^143 structurally and functionally undisclosed scFv VH domain polypeptides of 110 amino acids that are to have the functional property of binding GPC3; and
an infinite and/or enormously vast genus of about 3x10^304 and/or 4x10^119 structurally and functionally undisclosed additional elements of the chimeric antigen receptor, e.g. the transmembrane domain, the costimulatory domain(s), and the signal domain(s), and combinations and/or subcombinations thereof.
Applicant’s own work evidences that the GPC-3 chimeric antigen receptors do not function identically, nor achieve the same therapeutic result(s). For example, not all GPC-3 CAR constructs achieved a statistically meaningful prolonged survival of said mice, as evidenced by the amount of survival varying depending upon the other signaling components within the CAR construct, some being essentially identical to negative control (PBS or T cells lacking GPC-3 CAR), e.g. GPC3-4 BZ, GPC3-2 TZ, GPC3-1 TZ, GPC3-1 BZ, and GPC3-2 28BZ (Figure 10).
Therefore, based on the discussions above concerning the specific examples of structurally similar proteins that have different functions, along with the art's recognition that one cannot rely upon structural similarity alone to determine functionality, the specification fails to reasonably inform the ordinary artisan how to make and use the claimed enormously vast genus of about chimeric antigen receptors comprising:
about 8x10^150 structurally and functionally undisclosed scFv VH domain polypeptides of 116 amino acids that are to have the functional property of binding GPC3;
about 8x10^143 structurally and functionally undisclosed scFv VH domain polypeptides of 110 amino acids that are to have the functional property of binding GPC3; and
an infinite and/or enormously vast genus of about 3x10^304 and/or 4x10^119 structurally and functionally undisclosed additional elements of the chimeric antigen receptor, e.g. the transmembrane domain, the costimulatory domain(s), and the signal domain(s), and combinations and/or subcombinations thereof.
Those of ordinary skill in the art would immediately recognize that the specific VH and VL CDR1, CDR2, and CDR3 SEQ ID NO motifs are not representative of the chimeric antigen receptor genus because the genus is highly variant.
Disclosure of putative structures having a theorized function in the absence of experimental data demonstrating the theorized function is insufficient to demonstrate possession of a representative number of species 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 invention.
A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that “only describe[d] one type of structurally similar antibodies” that “are not representative of the full variety or scope of the genus.”).
Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) (“[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.”). “A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when … the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed.” In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004)
The Federal Circuit has explained that a specification cannot always support expansive claim language and satisfy the requirements of 35 U.S.C. 112 “merely by clearly describing one embodiment of the thing claimed.” LizardTech v. Earth Resource Mapping, Inc., 424 F.3d 1336, 1346, 76 USPQ2d 1731, 1733 (Fed. Cir. 2005).
For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are “representative of the full variety or scope of the genus,” or by the establishment of “a reasonable structure-function correlation.” Such correlations may be established “by the inventor as described in the specification,” or they may be “known in the art at the time of the filing date.” See AbbVie, 759 F.3d at 1300-01, 111 USPQ2d 1780, 1790-91 (Fed. Cir. 2014)
In Amgen, Inc., v. Sanofi (872 F.3d 1367 (2017)
At 1375, [T]he use of post-priority-date evidence to show that a patent does not disclose a representative number of species of a claimed genus is proper.
At 1377, [W]e questioned the propriety of the "newly characterized antigen" test and concluded that instead of "analogizing the antibody-antigen relationship to a `key in a lock,'" it was more apt to analogize it to a lock and "a ring with a million keys on it." Id. at 1352.
An adequate written description must contain enough information about the actual makeup of the claimed products — "a precise definition, such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other materials," which may be present in "functional" terminology "when the art has established a correlation between structure and function." Ariad, 598 F.3d at 1350. But both in this case and in our previous cases, it has been, at the least, hotly disputed that knowledge of the chemical structure of an antigen gives the required kind of structure-identifying information about the corresponding antibodies. See, e.g., J.A. 1241 (549:5-
16) (Appellants' expert Dr. Eck testifying that knowing "that an antibody binds to a particular amino acid on PCSK9 ... does not tell you anything at all about the structure of the antibody"); J.A. 1314 (836:9-11) (Appellees' expert Dr. Petsko being informed of Dr. Eck's testimony and responding that "[m]y opinion is that [he's] right"); Centocor, 636 F.3d at 1352 (analogizing the antibody-antigen relationship as searching for a key "on a ring with a million keys on it") (internal citations and quotation marks omitted).
In the instant case, knowing that the initial VH and VL amino acid sequence of SEQ ID NO’s 27-30 bind to GPC-3 does not tell you anything at all about the structure (amino acid sequences) of the enormously vast genus of about chimeric antigen receptors comprising:
about 8x10^150 structurally and functionally undisclosed scFv VH domain polypeptides of 116 amino acids that are to have the functional property of binding GPC3; and
about 8x10^143 structurally and functionally undisclosed scFv VH domain polypeptides of 110 amino acids that are to have the functional property of binding GPC3,
that necessarily and predictably bind to GPC3.
Knowing that the initial chimeric antigen receptor may further comprise a transmembrane domain, a costimulatory domain, and a signal domain does not tell you anything at all about the structure (amino acid sequences) of the enormously vast genus of chimeric antigen receptors comprising:
about 8x10^150 structurally and functionally undisclosed scFv VH domain polypeptides of 116 amino acids that are to have the functional property of binding GPC3;
about 8x10^143 structurally and functionally undisclosed scFv VH domain polypeptides of 110 amino acids that are to have the functional property of binding GPC3; and
an infinite and/or enormously vast genus of about 3x10^304 and/or 4x10^119 structurally and functionally undisclosed additional elements of the chimeric antigen receptor, e.g. the transmembrane domain, the costimulatory domain(s), and the signal domain(s), and combinations and/or subcombinations thereof.
In Amgen, Inc., v. Sanofi (U.S. Supreme Court, No. 21-757 (2023))
“Amgen seeks to monopolize an entire class of things defined by their function”.
“The record reflects that this class of antibodies does not include just the 26 that Amgen has described by their amino acid sequence, but a “vast” number of additional antibodies that it has not.”
“It freely admits that it seeks to claim for itself an entire universe of antibodies.”
In the instant case, the record reflects that the claimed class of anti-GPC3 chimeric antigen receptor variants encompasses an enormously vast genus of chimeric antigen receptors comprising:
about 8x10^150 structurally and functionally undisclosed scFv VH domain polypeptides of 116 amino acids that are to have the functional property of binding GPC3;
about 8x10^143 structurally and functionally undisclosed scFv VH domain polypeptides of 110 amino acids that are to have the functional property of binding GPC3; and
an infinite and/or enormously vast genus of about 3x10^304 and/or 4x10^119 structurally and functionally undisclosed additional elements of the chimeric antigen receptor, e.g. the transmembrane domain, the costimulatory domain(s), and the signal domain(s), and combinations and/or subcombinations thereof.
“They leave a scientist forced to engage in painstaking experimentation to see what works. 159 U.S., at 475.
This is not enablement. More nearly, it is “a hunting license”. Brenner v. Manson, 383 U.S. 519, 536 (1966).
“Amgen has failed to enable all that it has claimed, even allowing for a reasonable degree of experimentation”.
While the “roadmap” would produce functional combinations, it would not enable others to make and use the functional combinations; it would instead leave them to “random trial-and-error discovery”.
“Amgen offers persons skilled in the art little more than advice to engage in “trial and error”.
“The more a party claims for itself the more it must enable.”
“Section 112 of the Patent Act reflects Congress’s judg-ment that if an inventor claims a lot, but enables only a lit-tle, the public does not receive its benefit of the bargain. For more than 150 years, this Court has enforced the stat-utory enablement requirement according to its terms. If the Court had not done so in Incandescent Lamp, it might have been writing decisions like Holland Furniture in the dark. Today’s case may involve a new technology, but the legal principle is the same.
Applicant’s working examples are directed to scFv VH and VL amino acid sequences of SEQ ID NO’s: 27-30, and the nine chimeric antigen receptor species comprising the amino acid sequences of SEQ ID NO’s: 3-10 and 25.
Applicant is essentially requiring the ordinary artisans to discover for themselves that which Applicant fails to disclose.
Accordingly, this limited information is not deemed sufficient to reasonably convey to one skilled in the art that the applicant is in possession of the enormously vast genus of chimeric antigen receptors comprising:
about 8x10^150 structurally and functionally undisclosed scFv VH domain polypeptides of 116 amino acids that are to have the functional property of binding GPC3;
about 8x10^143 structurally and functionally undisclosed scFv VH domain polypeptides of 110 amino acids that are to have the functional property of binding GPC3; and
an infinite and/or enormously vast genus of about 3x10^304 and/or 4x10^119 structurally and functionally undisclosed additional elements of the chimeric antigen receptor, e.g. the transmembrane domain, the costimulatory domain(s), and the signal domain(s), and combinations and/or subcombinations thereof.
Thus, for the reasons outlined above, it is concluded that the claims do not meet the requirements for written description under 35 U.S.C. 112, first paragraph.
MPEP 2163 - 35 U.S.C. 112(a) and the first paragraph of pre-AIA 35 U.S.C. 112 require that the “specification shall contain a written description of the invention ....” This requirement is separate and distinct from the enablement requirement. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010) (en banc)
3. Claims 29 and 32-36 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.
The Examiner incorporates herein the above 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, written description rejection.
Claims 29 and 36 recite “an effective amount”.
The phrase “an effective amount” has been held to be indefinite when the claim fails to state the function which is to be achieved and more than one effect can be implied from the specification or the relevant art. In reFredericksen, 213 F.2d 547, 102 USPQ 35 (CCPA 1954). MPEP 2173.05(c)
A claim may be rendered indefinite by reference to an object that is variable. (MPEP §2173.05(b)).
A “therapeutically effective amount” is a functional property that is dependent upon many different variable parameters, including, but not limited to:
the type of subject human to be treated [parameter 1];
the structure(s) of chimeric antigen receptor [parameter 2];
the type of host cell comprising the chimeric antigen receptor [parameter 3];
the CAR-containing cell dosage administered [parameter 4];
the phenotypic response to be achieved [parameter 5];
the costimulatory domain(s) and signaling domain(s) structure(s) and/or combination(s) and/or subcombination(s) thereof present in the chimeric antigen receptor [parameter 6]; and
the type of cancer that is to be treated [parameter 7].
The claim(s) also denote(s) that there is an amount of the pharmaceutical composition comprising the cells comprising the anti-GPC3 chimeric antigen receptor that, upon administration to the subject, is not, in fact, “a therapeutically effective amount”.
Parameter 1
Applicant has amended the independent claim to recite a human subject.
Parameter 2
As discussed above, the independent claims reasonably encompass chimeric antigen receptors comprising:
about 8x10^150 structurally and functionally undisclosed scFv VH domain polypeptides of 116 amino acids that are to have the functional property of binding GPC3;
about 8x10^143 structurally and functionally undisclosed scFv VH domain polypeptides of 110 amino acids that are to have the functional property of binding GPC3; and
an infinite (501-226 = 275; 20^275 = infinite) and/or enormously vast genus of about 3x10^304 and/or 4x10^119 (460-226 = 234; 20^234 = 3x10^304; 318-226 = 92; 20^92 = 4x10^119) structurally and functionally undisclosed additional elements of the chimeric antigen receptor, e.g. a transmembrane domain, a costimulatory domain, and a signal domain.
However, only the two species of GPC3-1 and GPC3-2 scFv antigen-binding domain amino acid sequences, SEQ ID NO: 1 and SEQ ID NO:2, respectively, encoded by the nucleotide sequences of SEQ ID NO:33 and SEQ ID NO:34, respectively, are disclosed.
The claim fails to recite, and the specification fails to disclose, a first anti-GPC3 chimeric antigen receptor whose antigen binding domain encoded by the nucleotide sequence of SEQ ID NO:33 or SEQ ID NO:34 that does not have the functional property of does not induce cytokine production in GPC3-cells as opposed to a second anti-GPC3 chimeric antigen receptor whose antigen binding domain encoded by the nucleotide sequence of SEQ ID NO:33 or SEQ ID NO:34 has the functional property of does induce cytokine production in GPC3-cells, for example.
The claim fails to recite, and the specification fails to disclose, how to transform or otherwise modify a first anti-GPC3 chimeric antigen receptor whose antigen binding domain encoded by the nucleotide sequence of SEQ ID NO:33 or SEQ ID NO:34 that does induce cytokine production in GPC3-cells, into a second anti-GPC3 chimeric antigen receptor whose antigen binding domain encoded by the nucleotide sequence of SEQ ID NO:33 or SEQ ID NO:34 that now, necessarily and predictably has the functional property of does not induce cytokine production in GPC3-cells, for example.
Parameter 3
The claims are broad for encompassing an enormous genus of structurally and functionally different autologous human host cells, e.g. non-immune cell types, including fibroblast, muscle, endothelial, pancreatic, bladder, kidney, lung, and/or neural cells, and a genus of immune cell types, including dendritic, macrophage, B or T cells, comprising the enormously vast genus of chimeric antigen receptors comprising:
about 8x10^150 structurally and functionally undisclosed scFv VH domain polypeptides of 116 amino acids that are to have the functional property of binding GPC3;
about 8x10^143 structurally and functionally undisclosed scFv VH domain polypeptides of 110 amino acids that are to have the functional property of binding GPC3; and
an infinite and/or enormously vast genus of about 3x10^304 and/or 4x10^119 structurally and functionally undisclosed additional elements of the chimeric antigen receptor, e.g. the transmembrane domain, the costimulatory domain(s), and the signal domain(s), and combinations and/or subcombinations thereof, respectively.
The specification discloses the host cells may be T cells, alpha/beta T cells, gamma/delta T cells, cytotoxic T cells, regulatory T cells, NK cells, NKT cells, or iNKT cells, (e.g. [0105]).
Parameter 4
The claims are broad for encompassing an enormous genus of the CAR-containing cell dosages to be administered [parameter 4] to the enormous genus of about 1x10^6 animal species of animals.
The specification discloses administering about 4x10^6 GPC3-1 or GPC3-2 CAR T cells to a mouse subject (e.g. Example 4).
Parameter 5
Applicant has amended the independent claim to recite the effective amount achieves the result of prolonging the survival of the human subject.
It is understood that in order to meaningfully treat the subject, and thereby satisfy the requirements of 35 U.S.C. 101 (See MPEP 2107.01 III, Therapeutic or Pharmacological Utility), a therapeutically effective amount or dose of the enormous genus of autologous human host cells, e.g. non-immune cell types, including fibroblast, muscle, endothelial, pancreatic, bladder, kidney, lung, and/or neural cells, and a genus of immune cell types, including dendritic, macrophage, B or T cells, expressing the enormously vast genus of chimeric antigen receptors comprising:
about 8x10^150 structurally and functionally undisclosed scFv VH domain polypeptides of 116 amino acids that are to have the functional property of binding GPC3;
about 8x10^143 structurally and functionally undisclosed scFv VH domain polypeptides of 110 amino acids that are to have the functional property of binding GPC3; and
an infinite and/or enormously vast genus of about 3x10^304 and/or 4x10^119 structurally and functionally undisclosed additional elements of the chimeric antigen receptor, e.g. the transmembrane domain, the costimulatory domain(s), and the signal domain(s), and combinations and/or subcombinations thereof, respectively, that must be administered to the human subjects/patients, thereby achieving some real-world, clinically and statistically meaningful effect, including, but not limited to, prolonging survival, and thereby being of “immediate benefit to the public”.
Parameter 6
The breadth of the claims are enormously broad for reciting an enormously vast genus of chimeric antigen receptors comprising:
about 8x10^150 structurally and functionally undisclosed scFv VH domain polypeptides of 116 amino acids that are to have the functional property of binding GPC3;
about 8x10^143 structurally and functionally undisclosed scFv VH domain polypeptides of 110 amino acids that are to have the functional property of binding GPC3; and
an infinite and/or enormously vast genus of about 3x10^304 and/or 4x10^119 structurally and functionally undisclosed additional elements of the chimeric antigen receptor, e.g. the transmembrane domain, the costimulatory domain(s), and the signal domain(s), and combinations and/or subcombinations thereof, respectively, that must be administered to the human subjects/patients, thereby achieving some real-world, clinically and statistically meaningful effect, including, but not limited to, prolonging survival, and thereby being of “immediate benefit to the public”.
The ordinary artisan would immediately recognize that the GPC-3 antigen binding domain of the CAR, while necessary for target antigen recognition and binding, is, in and of itself, not dispositive for, nor controlling over, the therapeutic efficacy of the host cell expressing said CAR. Rather, the art recognizes that there have been multiple generations of CAR designs using different transmembrane domains, different costimulatory domain(s), and different signaling domain(s), and combinations and/or subcombinations thereof, as each CAR design yields different phenotypic and physiological immune responses in the host T cell, which then also affects the ability of the CAR T cell to achieve a clinically meaningful treatment of the target cancer.
Applicant’s own work evidences that the GPC-3 chimeric antigen receptors do not function identically.
For example, the GPC-3 CAR constructs elicit different IFNgamma, IL-2, and/or TNFalpha responses when cultured with etiologically different tumor cell types (e.g. Figures 4A-B).
While some GPC-3 CAR constructs are “cytotoxic only to cells expressing GPC-3”, other CAR constructs were “cytotoxic to both GPC-3 positive cells and GPC-3 negative cells” (e.g. Figure 5, [0158]).
Applicant’s own work evidences that the GPC-3 chimeric antigen receptors do not function identically, nor achieve the same therapeutic result(s). For example, not all GPC-3 CAR constructs achieved a statistically meaningful reduction of tumor volume in the mouse tumor xenograft model, as evidenced by tumor volume varying depending upon the other signaling components within the CAR construct, some being essentially identical to negative control (PBS or T cells lacking GPC-3 CAR), e.g. GPC3-4 BZ, GPC3-2 TZ, and GPC3-1 TZ (Figure 9).
Not all GPC-3 CAR constructs achieved a statistically meaningful prolonged survival of said mice, as evidenced by the amount of survival varying depending upon the other signaling components within the CAR construct, some being essentially identical to negative control (PBS or T cells lacking GPC-3 CAR), e.g. GPC3-4 BZ, GPC3-2 TZ, GPC3-1 TZ, GPC3-1 BZ, and GPC3-2 28BZ (e.g. Figures 10 and 14).
Thus, the ordinary artisan would immediately recognize that a different dosage of the CAR-expressing host cells must be administered to the human cancer patient, depending on the specific type of, at least, the costimulatory domain(s) and signaling domain(s), and combinations and/or subcombinations thereof, present in the CAR construct.
Parameter 7
The breadth of the claims encompasses an enormously vast genus of etiologically and pathologically distinct cancers, including, but not limited to NSCLC, advanced solid malignancies, biliary tract neoplasms, bladder cancer, colorectal cancer, diffuse large B-cell lymphoma, esophageal neoplasms, esophageal squamous cell carcinoma, extensive stage small cell lung cancer, gastric adenocarcinoma, gastric cancer, gastroesophageal junction cancer, head and neck cancer, head and neck squamous cell carcinoma, hepatocellular carcinoma, Hodgkin lymphoma, lung cancer, melanoma, mesothelioma, metastatic clear cell renal carcinoma, metastatic melanoma, metastatic non-cutaneous melanoma, multiple myeloma, nasopharyngeal neoplasms, non-Hodgkin lymphoma, ovarian cancer, fallopian tube cancer, peritoneal neoplasms, pleural mesothelioma, prostatic neoplasms, recurrent or metastatic PD-Ll positive or negative SCCHN, recurrent squamous cell lung cancer, renal cell cancer, renal cell carcinoma, SCCHN, hypopharyngeal squamous cell carcinoma, laryngeal squamous cell carcinoma, small cell lung cancer, squamous cell carcinoma of the head and neck, squamous cell lung carcinoma, TNBC, transitional cell carcinoma, unresectable or metastatic melanoma, urothelial cancer, and urothelial carcinoma [0123].
Applicant’s own work evidences that the GPC-3 chimeric antigen receptors do not function identically in response to GPC-3 expressing cancers.
For example, it is recognized that different cancers express different levels of GPC-3, e.g. low level vs high level. The GPC-3 CAR constructs elicit different cytotoxic immune responses, depending upon their corresponding effector cell: target cell ratio when cultured with etiologically different tumor cell types (e.g. Figure 5).
Thus, the ordinary artisan would immediately recognize that a different dosage of the CAR-expressing host cells must be administered to the human cancer patient, depending on the type of cancer and the relative amount of GPC-3 expression by said cancer, e.g.:
a first human cancer patient having a first type of GPC-3 expressing cancer, e.g. low level GPC-3 expression, as opposed to
a second human cancer patient having a second type of GPC-3 expressing cancer, e.g. moderate level GPC-3 expression, as opposed to
a third human cancer patient having a third type of GPC-3 expressing cancer, e.g. high level GPC-3 expression, for example.
The GPC-3 CAR constructs elicit different IFNgamma, IL-2, and/or TNFalpha responses when cultured with etiologically different tumor cell types that express different levels of GPC-3 target antigen, including cancer cells that do not express GPC-3 (e.g. Figures 4A-B).
While some GPC-3 CAR constructs are “cytotoxic only to cells expressing GPC-3”, other CAR constructs were “cytotoxic to both GPC-3 positive cells and GPC-3 negative cells” (e.g. Figure 5, [0158]).
It is apparent that the amount must be therapeutic. Even so, the various endpoints and extents that define effective treatment are more of a conditional or qualitative nature, especially in the situation when it is not the tumor that is being treated, but the patient. As such, it is not evident what effect is necessarily achieved. Rather, the expected or desired effect that is to be achieved in the practice of the claimed invention to treat the patient is considered highly subjective and would tend to vary substantially.
The recitation implies a genus of unrecited and undisclosed phenotypes by which the therapeutically effective dose is to be determined and/or identified, thereby rendering the claim indefinite. A claim may be rendered indefinite by reference to an object that is variable. (MPEP §2173.05(b)).
The specification discloses the effective amount is sufficient to achieve an intended purpose, which itself is an arbitrary and subjective determination, determined empirically [092], including, but not limited to, minimizing risk of cytokine release syndrome (CRS) [093], inhibiting neoplastic cell growth or metastasis [0122], reducing disease pathology, reducing or eliminating disease symptoms, promoting increased survival rates, reducing discomfort, mitigating or decreasing at least one clinical symptom, inhibit or delay the progression of the condition, and/or prevent or delay onset of disease or illness [090].
If there are multiple ways to measure “therapeutically effective dose”, to wit, concentration, time after administration, and/or phenotypic result, yet each yields a different result, then the claim may be indefinite because it is unclear which method is to be performed to determine infringement.
The specification discloses administering about 4x10^6 GPC3-1 or GPC3-2 CAR T cells to a mouse subject (e.g. Example 4), whereby GPC3-2 CAR T cells were not tolerated at an equivalent dose to the GPC3-1 CAR T cells [0164].
The phrase “prolongs survival of the human subject” in Claim 29 is a relative term which renders the claim indefinite. The phrase “prolongs survival of the human subject” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
A claim may be rendered indefinite by reference to an object that is variable. (MPEP §2173.05(b)).
The breadth of the claims encompasses an enormously vast genus of structurally and functionally distinct CAR cell immunotherapy compositions and administration regimens. The specification discloses the CAR cell immunotherapy regimen may be administered alone, or with additional therapeutic agents, such as cytokines (disclosed at a high level of generality), anticancer antibodies, chemotherapeutic agents, and/or additional cell types (disclosed at a high level of generality) [0125, 127].
The breadth of the claims encompasses an enormously vast genus of temporal variable as to when the GPC-CAR cell immunotherapy dosage and regimen is/are to be administered, from which ‘prolong survival’ is to be determined. For example, the GPC-CAR cell immunotherapy dosage and regimen is/are administered in early stage diagnosis, in the absence of other cancer therapy treatments, after failure of first-line cancer therapy, late stage cancer disease, relapse/recurring aggressive cancer disease, etc… The GPC-CAR cell immunotherapy dosage and regimen is/are administered once, twice, more than three times, more than five times, etc…
Those of ordinary skill in the art have long-recognized that each human cancer patient responds differently to their type of cancer and cancer treatment modalities. The ordinary artisan immediately recognizes that one simply cannot know how long the human cancer subject will survive in the absence of the enormous genus of autologous human host cells, e.g. non-immune cell types, including fibroblast, muscle, endothelial, pancreatic, bladder, kidney, lung, and/or neural cells, and a genus of immune cell types, including dendritic, macrophage, B or T cells, expressing the enormously vast genus of chimeric antigen receptors comprising:
about 8x10^150 structurally and functionally undisclosed scFv VH domain polypeptides of 116 amino acids that are to have the functional property of binding GPC3;
about 8x10^143 structurally and functionally undisclosed scFv VH domain polypeptides of 110 amino acids that are to have the functional property of binding GPC3; and
an infinite and/or enormously vast genus of about 3x10^304 and/or 4x10^119 structurally and functionally undisclosed additional elements of the chimeric antigen receptor, e.g. the transmembrane domain, the costimulatory domain(s), and the signal domain(s), and combinations and/or subcombinations thereof, respectively, that must be administered to the human subjects/patients, thereby achieving some real-world, clinically and statistically meaningful effect, including, but not limited to, prolonging survival, from which to compare ‘prolonged survival’ upon treatment, because it is the same human subject. One simply cannot go back in time after the human subject has died from their cancer, and then decide when during their cancer disease, and by what dosage and administration regimen, the CAR cell therapy is to be performed on the human subject thereby necessarily and predictably prolonging their survival, as such violates the natural law of temporal mechanics, as is understood by modern society. One simply cannot a priori know the future, as such violates the natural law of temporal mechanics, as is understood by modern society.
The claims fail to recite, and the specification fails to disclose, a first dosage [parameter 4] of a first host cell [parameter 3], e.g. pancreatic cell, expressing a first chimeric antigen receptor [parameter 2a] of an enormously vast genus of structurally and functionally distinct chimeric antigen receptors comprising a first GPC3 antigen binding domain [parameter 2b] of the essentially infinite genus of structurally and functionally undisclosed antigen binding domains and/or the enormously expressing the enormously vast genus of chimeric antigen receptors comprising:
about 8x10^150 structurally and functionally undisclosed scFv VH domain polypeptides of 116 amino acids that are to have the functional property of binding GPC3;
about 8x10^143 structurally and functionally undisclosed scFv VH domain polypeptides of 110 amino acids that are to have the functional property of binding GPC3; and
an infinite and/or enormously vast genus of about 3x10^304 and/or 4x10^119 structurally and functionally undisclosed additional elements of the chimeric antigen receptor, e.g. the transmembrane domain, the costimulatory domain(s), and the signal domain(s), and combinations and/or subcombinations thereof, respectively [parameter 6], that, upon administration to a first human subject/patient [parameter 1], will necessarily and predictably achieve the functional property [parameter 5] of reducing discomfort of a first cancer and it’s corresponding amount of GPC-3 expression level [parameter 7], e.g. metastatic ovarian cancer disease, but not prolonging survival, as opposed to a second dosage [parameter 4] of a second host cell [parameter 3], e.g. a muscle cell, expressing a second chimeric antigen receptor [parameter 2a] of an enormously vast genus of structurally and functionally distinct chimeric antigen receptors comprising a first GPC3 antigen binding domain [parameter 2b] of the enormously vast genus of chimeric antigen receptors comprising:
about 8x10^150 structurally and functionally undisclosed scFv VH domain polypeptides of 116 amino acids that are to have the functional property of binding GPC3;
about 8x10^143 structurally and functionally undisclosed scFv VH domain polypeptides of 110 amino acids that are to have the functional property of binding GPC3; and
an infinite and/or enormously vast genus of about 3x10^304 and/or 4x10^119 structurally and functionally undisclosed additional elements of the chimeric antigen receptor, e.g. the transmembrane domain, the costimulatory domain(s), and the signal domain(s), and combinations and/or subcombinations thereof, respectively [parameter 6], that, upon administration to a second human subject/patient [parameter 1] will necessarily and predictably achieve the functional property [parameter 5] of prolonging survival, but not minimizing risk of cytokine release syndrome (CRS) or eliminate a second cancer and it’s corresponding amount of GPC-3 expression level [parameter 7], e.g. metastatic lung cancer disease, for example.
The claims fail to recite, and the specification fails to disclose, a first dosage [parameter 4] of a first host cell [parameter 3], e.g. a neural cell, expressing a first chimeric antigen receptor [parameter 2a] of an enormously vast genus of structurally and functionally distinct chimeric antigen receptors comprising a first GPC3 antigen binding domain [parameter 2b] of the essentially infinite genus of structurally and functionally undisclosed antigen binding domains and/or the enormously vast genus of chimeric antigen receptors comprising:
about 8x10^150 structurally and functionally undisclosed scFv VH domain polypeptides of 116 amino acids that are to have the functional property of binding GPC3;
about 8x10^143 structurally and functionally undisclosed scFv VH domain polypeptides of 110 amino acids that are to have the functional property of binding GPC3; and
an infinite and/or enormously vast genus of about 3x10^304 and/or 4x10^119 structurally and functionally undisclosed additional elements of the chimeric antigen receptor, e.g. the transmembrane domain, the costimulatory domain(s), and the signal domain(s), and combinations and/or subcombinations thereof, respectively [parameter 6], that, upon administration to a first human subject/patient [parameter 1] will necessarily and predictably achieve the functional property [parameter 5] of mitigating at least one symptom of a first cancer and it’s corresponding amount of GPC-3 expression level [parameter 7], e.g. hepatocellular carcinoma disease, but not promote increased lifespan (syn. prolong survival), as opposed to a second dosage [parameter 4] of a second host cell [parameter 3], e.g. a fibroblast cell, expressing a second chimeric antigen receptor [parameter 2a] of an enormously vast genus of structurally and functionally distinct chimeric antigen receptors comprising a first GPC3 antigen binding domain [parameter 2b] of the enormously vast genus of chimeric antigen receptors comprising:
about 8x10^150 structurally and functionally undisclosed scFv VH domain polypeptides of 116 amino acids that are to have the functional property of binding GPC3;
about 8x10^143 structurally and functionally undisclosed scFv VH domain polypeptides of 110 amino acids that are to have the functional property of binding GPC3; and
an infinite and/or enormously vast genus of about 3x10^304 and/or 4x10^119 structurally and functionally undisclosed additional elements of the chimeric antigen receptor, e.g. the transmembrane domain, the costimulatory domain(s), and the signal domain(s), and combinations and/or subcombinations thereof, respectively [parameter 6], that, upon administration to a second human subject/patient [parameter 1] will necessarily and predictably achieve the functional property [parameter 5] of prolonging survival, but not eliminating a second cancer and it’s corresponding amount of GPC-3 expression level [parameter 7], e.g. gastric adenocarcinoma tumor/cancer disease, for example.
The claims fail to recite, and the specification fails to disclose, a first dosage [parameter 4] of a first host cell [parameter 3], e.g. a dendritic cell, expressing a first chimeric antigen receptor [parameter 2a] of an enormously vast genus of structurally and functionally distinct chimeric antigen receptors comprising a first GPC3 antigen binding domain [parameter 2b] of the essentially infinite genus of structurally and functionally undisclosed antigen binding domains and/or the enormously vast genus of chimeric antigen receptors comprising:
about 8x10^150 structurally and functionally undisclosed scFv VH domain polypeptides of 116 amino acids that are to have the functional property of binding GPC3;
about 8x10^143 structurally and functionally undisclosed scFv VH domain polypeptides of 110 amino acids that are to have the functional property of binding GPC3; and
an infinite and/or enormously vast genus of about 3x10^304 and/or 4x10^119 structurally and functionally undisclosed additional elements of the chimeric antigen receptor, e.g. the transmembrane domain, the costimulatory domain(s), and the signal domain(s), and combinations and/or subcombinations thereof, respectively [parameter 6], that, upon administration to a first human subject/patient [parameter 1] will necessarily and predictably achieve the functional property [parameter 5] of mitigating at least one symptom of a first cancer and it’s corresponding amount of GPC-3 expression level [parameter 7], e.g. mesothelioma disease, but not promote increased lifespan (syn. prolong survival), as opposed to a second dosage [parameter 4] of a second host cell [parameter 3], e.g. a B cell, expressing a second chimeric antigen receptor [parameter 2a] of an enormously vast genus of structurally and functionally distinct chimeric antigen receptors comprising a first GPC3 antigen binding domain [parameter 2b] of the essentially infinite genus of structurally and functionally undisclosed antigen binding domains and/or the enormously vast genus of chimeric antigen receptors comprising:
about 8x10^150 structurally and functionally undisclosed scFv VH domain polypeptides of 116 amino acids that are to have the functional property of binding GPC3;
about 8x10^143 structurally and functionally undisclosed scFv VH domain polypeptides of 110 amino acids that are to have the functional property of binding GPC3; and
an infinite and/or enormously vast genus of about 3x10^304 and/or 4x10^119 structurally and functionally undisclosed additional elements of the chimeric antigen receptor, e.g. the transmembrane domain, the costimulatory domain(s), and the signal domain(s), and combinations and/or subcombinations thereof, respectively [parameter 6], that, upon administration to a second human subject/patient [parameter 1] will necessarily and predictably achieve the functional property [parameter 5] of prolonging survival, but not eliminating a second cancer and it’s corresponding amount of GPC-3 expression level [parameter 7], e.g. multiple myeloma disease, for example.
The specification discloses the anti-TNFalpha antibody is to attenuate CAR T toxicity and/or promote anti-tumor activity at higher CAR T doses (e.g. [074]), or attenuate weight loss or CRS-like symptoms [0126].
The specification discloses a working example of administering 100ug of anti-human TNFalpha antibody to mouse subjects (e.g. [0188]), which abolished the efficacy of a GPC3-1-containing CAR [0190].
Norelli et al (Clinical pharmacology of CAR-T cells: Linking cellular pharmacodynamics to pharmacokinetics and antitumor effects, Biochimica et Biophys. Acta 1865: 90-100, 2016) is considered relevant prior art for having taught the step of administering anti-TNFalpha antibodies to those subjects who are receiving CAR T therapy for the treatment of cancer (e.g. pg 97, col. 2) because those of ordinary skill in the art previously recognized that a common and potentially severe side-effect of CAR T cell therapy is cytokine release syndrome (CRS), which often leads to end-stage multi-organ insufficiency, and that attempts to control CRS include the use of anti-TNFalpha antibodies. However, most such attempts have been largely ineffective.
The claims fail to recite, and the specification fails to disclose, a first anti-TNFalpha antibody dosage that, upon administration to a first human subject/patient [parameter 1], will necessarily and predictably achieve the functional property [parameter 5] of attenuating weight loss, but not promote higher CAR T doses, as opposed to a second anti-TNFalpha antibody dosage that, upon administration to a second human subject/patient [parameter 1], will necessarily and predictably achieve the functional property [parameter 5] of attenuate CRS-like symptoms, but not promote anti-tumor activity at higher CAR T doses, for example.
The instant claims as a whole do not apprise one of ordinary skill in the art of its scope and, therefore, does not serve the notice function required by 35 U.S.C. 112, second paragraph, by providing clear warning to others as to what constitutes infringement of the patent.
Dependent claims are included in the basis of the rejection because they do not correct the primary deficiencies of the independent claim.
Response to Arguments
Applicant iterates prior argument.
The Examiner responded to the prior argument in the prior Office Action.
The claims continue to suffer indefiniteness by reference to an object(s) that is/are variable. (MPEP §2173.05(b)).
A “therapeutically effective amount” is a functional property that is dependent upon many different variable parameters, including, but not limited to:
the type of subject human to be treated [parameter 1];
the structure(s) of chimeric antigen receptor [parameter 2];
the type of host cell comprising the chimeric antigen receptor [parameter 3];
the CAR-containing cell dosage administered [parameter 4];
the phenotypic response to be achieved [parameter 5];
the costimulatory domain(s) and signaling domain(s) structure(s) and/or combination(s) and/or subcombination(s) thereof present in the chimeric antigen receptor [parameter 6]; and
the type of cancer that is to be treated [parameter 7].
The claim(s) also denote(s) that there is an amount of the pharmaceutical composition comprising the cells comprising the anti-GPC3 chimeric antigen receptor that, upon administration to the subject, is not, in fact, “a therapeutically effective amount”.
4. Claims 29 and 32-36 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.
Claims 29 and 36 recite “an effective amount”.
The Examiner incorporates herein the above 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, written description and 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, rejections.
The phrase “an effective amount” has been held to be indefinite when the claim fails to state the function which is to be achieved and more than one effect can be implied from the specification or the relevant art. In reFredericksen, 213 F.2d 547, 102 USPQ 35 (CCPA 1954). MPEP 2173.05(c)
A claim may be rendered indefinite by reference to an object that is variable. (MPEP §2173.05(b)).
A “therapeutically effective amount” is a functional property that is dependent upon many different variable parameters, including, but not limited to:
the type of subject human to be treated [parameter 1];
the structure(s) of chimeric antigen receptor [parameter 2];
the type of host cell comprising the chimeric antigen receptor [parameter 3];
the CAR-containing cell dosage administered [parameter 4];
the phenotypic response to be achieved [parameter 5];
the costimulatory domain(s) and signaling domain(s) structure(s) and/or combination(s) and/or subcombination(s) thereof present in the chimeric antigen receptor [parameter 6]; and
the type of cancer that is to be treated [parameter 7].
The claim(s) also denote(s) that there is an amount of the pharmaceutical composition comprising the cells comprising the anti-GPC3 chimeric antigen receptor that, upon administration to the subject, is not, in fact, “a therapeutically effective amount”.
In Amgen, Inc., v. Sanofi (872 F.3d 1367 (2017)
At 1375, [T]he use of post-priority-date evidence to show that a patent does not disclose a representative number of species of a claimed genus is proper.
At 1377, [W]e questioned the propriety of the "newly characterized antigen" test and concluded that instead of "analogizing the antibody-antigen relationship to a `key in a lock,'" it was more apt to analogize it to a lock and "a ring with a million keys on it." Id. at 1352.
An adequate written description must contain enough information about the actual makeup of the claimed products — "a precise definition, such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other materials," which may be present in "functional" terminology "when the art has established a correlation between structure and function." Ariad, 598 F.3d at 1350. But both in this case and in our previous cases, it has been, at the least, hotly disputed that knowledge of the chemical structure of an antigen gives the required kind of structure-identifying information about the corresponding antibodies. See, e.g., J.A. 1241 (549:5-
16) (Appellants' expert Dr. Eck testifying that knowing "that an antibody binds to a particular amino acid on PCSK9 ... does not tell you anything at all about the structure of the antibody"); J.A. 1314 (836:9-11) (Appellees' expert Dr. Petsko being informed of Dr. Eck's testimony and responding that "[m]y opinion is that [he's] right"); Centocor, 636 F.3d at 1352 (analogizing the antibody-antigen relationship as searching for a key "on a ring with a million keys on it") (internal citations and quotation marks omitted).
In the instant case, knowing that the initial VH and VL amino acid sequence of SEQ ID NO’s 27-30 bind to GPC-3 does not tell you anything at all about the structure (amino acid sequences) of the enormously vast genus of about chimeric antigen receptors comprising:
about 8x10^150 structurally and functionally undisclosed scFv VH domain polypeptides of 116 amino acids that are to have the functional property of binding GPC3; and
about 8x10^143 structurally and functionally undisclosed scFv VH domain polypeptides of 110 amino acids that are to have the functional property of binding GPC3,
that necessarily and predictably bind to GPC3.
Knowing that the initial chimeric antigen receptor may further comprise a transmembrane domain, a costimulatory domain, and a signal domain does not tell you anything at all about the structure (amino acid sequences) of the enormously vast genus of chimeric antigen receptors comprising:
about 8x10^150 structurally and functionally undisclosed scFv VH domain polypeptides of 116 amino acids that are to have the functional property of binding GPC3;
about 8x10^143 structurally and functionally undisclosed scFv VH domain polypeptides of 110 amino acids that are to have the functional property of binding GPC3; and
an infinite and/or enormously vast genus of about 3x10^304 and/or 4x10^119 structurally and functionally undisclosed additional elements of the chimeric antigen receptor, e.g. the transmembrane domain, the costimulatory domain(s), and the signal domain(s), and combinations and/or subcombinations thereof.
Applicant’s own work evidences that the GPC-3 chimeric antigen receptors do not function identically, nor achieve the same therapeutic result(s). For example, not all GPC-3 CAR constructs achieved a statistically meaningful prolonged survival of said mice, as evidenced by the amount of survival varying depending upon the other signaling components within the CAR construct, some being essentially identical to negative control (PBS or T cells lacking GPC-3 CAR), e.g. GPC3-4 BZ, GPC3-2 TZ, GPC3-1 TZ, GPC3-1 BZ, and GPC3-2 28BZ (Figure 10).
Applicant is essentially requiring the ordinary artisans to discover for themselves that which Applicant fails to disclose.
In Amgen, Inc., v. Sanofi (U.S. Supreme Court, No. 21-757 (2023))
“Amgen seeks to monopolize an entire class of things defined by their function”.
“The record reflects that this class of antibodies does not include just the 26 that Amgen has described by their amino acid sequence, but a “vast” number of additional antibodies that it has not.”
“It freely admits that it seeks to claim for itself an entire universe of antibodies.”
In the instant case, the record reflects that the claimed class of anti-GPC3 chimeric antigen receptor molecule variants encompasses an enormously vast genus of chimeric antigen receptors comprising:
about 8x10^150 structurally and functionally undisclosed scFv VH domain polypeptides of 116 amino acids that are to have the functional property of binding GPC3;
about 8x10^143 structurally and functionally undisclosed scFv VH domain polypeptides of 110 amino acids that are to have the functional property of binding GPC3; and
an infinite and/or enormously vast genus of about 3x10^304 and/or 4x10^119 structurally and functionally undisclosed additional elements of the chimeric antigen receptor, e.g. the transmembrane domain, the costimulatory domain(s), and the signal domain(s), and combinations and/or subcombinations thereof.
“They leave a scientist forced to engage in painstaking experimentation to see what works. 159 U.S., at 475.
This is not enablement. More nearly, it is “a hunting license”. Brenner v. Manson, 383 U.S. 519, 536 (1966).
“Amgen has failed to enable all that it has claimed, even allowing for a reasonable degree of experimentation”.
While the “roadmap” would produce functional combinations, it would not enable others to make and use the functional combinations; it would instead leave them to “random trial-and-error discovery”.
“Amgen offers persons skilled in the art little more than advice to engage in “trial and error”.
“The more a party claims for itself the more it must enable.”
“Section 112 of the Patent Act reflects Congress’s judg-ment that if an inventor claims a lot, but enables only a lit-tle, the public does not receive its benefit of the bargain. For more than 150 years, this Court has enforced the stat-utory enablement requirement according to its terms. If the Court had not done so in Incandescent Lamp, it might have been writing decisions like Holland Furniture in the dark. Today’s case may involve a new technology, but the legal principle is the same.
Applicant’s working examples are directed to scFv VH and VL amino acid sequences of SEQ ID NO’s: 27-30, and the nine chimeric antigen receptor species comprising the amino acid sequences of SEQ ID NO’s: 3-10 and 25.
However, Applicant’s own work evidences that not all of these GPC-3 chimeric antigen receptors function identically, nor achieve the same therapeutic result(s). For example, not all GPC-3 CAR constructs achieved a statistically meaningful prolonged survival of said mice, as evidenced by the amount of survival varying depending upon the other signaling components within the CAR construct, some being essentially identical to negative control (PBS or T cells lacking GPC-3 CAR), e.g. GPC3-4 BZ, GPC3-2 TZ, GPC3-1 TZ, GPC3-1 BZ, and GPC3-2 28BZ (Figure 10).
Applicant is essentially requiring the ordinary artisans to discover for themselves that which Applicant fails to disclose.
Only CAR T host cells, administered to a mouse subject at a dose of at least 4x10^6 GPC3-CAR T cells is disclosed.
MPEP 2163 - 35 U.S.C. 112(a) and the first paragraph of pre-AIA 35 U.S.C. 112 require that the “specification shall contain a written description of the invention ....” This requirement is separate and distinct from the enablement requirement. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010) (en banc)
Dependent claims are included in the basis of the rejection because they do not correct the primary deficiencies of the independent claim(s).
Response to Arguments
Applicant iterates prior argument.
The Examiner responded to the prior argument in the prior Office Action.
5. Claims 29 and 32-36 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 method of inhibiting tumor growth, inducing tumor regression, and/or prolonging survival in a mouse subject suffering from a GPC3-expressing cancer, the method comprising the step(s) of:
i) administering to said mouse subject a pharmaceutical composition comprising at least 4x10^6 T cells expressing a chimeric antigen receptor comprising a transmembrane domain, a costimulatory domain, an intracellular signaling domain, and the GPC3 antigen-binding domain amino acid sequences of SEQ ID NO: 1 and SEQ ID NO:2,
does not reasonably provide enablement for an enormously vast genus of dosages [parameter 4] of an enormous genus of structurally and functionally distinct host cells [parameter 3], expressing an enormous genus of structurally and functionally undisclosed chimeric antigen receptors [parameter 2a] comprising the enormously vast genus of chimeric antigen receptors comprising:
about 8x10^150 structurally and functionally undisclosed scFv VH domain polypeptides of 116 amino acids that are to have the functional property of binding GPC3;
about 8x10^143 structurally and functionally undisclosed scFv VH domain polypeptides of 110 amino acids that are to have the functional property of binding GPC3 [parameter 2b]; and
an infinite and/or enormously vast genus of about 3x10^304 and/or 4x10^119 structurally and functionally undisclosed additional elements of the chimeric antigen receptor, e.g. the transmembrane domain, the costimulatory domain(s), and the signal domain(s), and combinations and/or subcombinations thereof, respectively [parameter 6], that, upon administration to human subjects/patients [parameter 1] will necessarily and predictably achieve the functional property(ies) [parameter 5] of an intended purpose, e.g. prolonging survival, which itself is an arbitrary and subjective determination, determined empirically, including, but not limited to, minimizing risk of cytokine release syndrome (CRS), inhibiting neoplastic cell growth or metastasis, reducing disease pathology, reducing or eliminating disease symptoms, promoting increased survival rates, reducing discomfort, mitigating or decreasing at least one clinical symptom, inhibit or delay the progression of the condition, and/or prevent or delay onset of disease or illness for the enormous genus of etiologically and pathologically distinct cancers, each of which naturally expresses different levels of the target GPC-3 antigen, e.g. low, moderate, or high [parameter 7].
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
While determining whether a specification is enabling, one considers whether the claimed invention provides sufficient guidance to make and use the claimed invention. If not, whether an artisan would have required undue experimentation to make and use the claimed invention and whether working examples have been provided. When determining whether a specification meets the enablement requirements, some of the factors that need to be analyzed are: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, and whether the quantity of any necessary experimentation to make or use the invention based on the content of the disclosure is “undue” (In re Wands, 858 F.2d 731, 737, 8 USPQ2ds 1400, 1404 (Fed. Cir. 1988)). Furthermore, USPTO does not have laboratory facilities to test if an invention will function as claimed when working examples are not disclosed in the specification. Therefore, enablement issues are raised and discussed based on the state of knowledge pertinent to an art at the time of the invention. And thus, skepticism raised in the enablement rejections are those raised in the art by artisans of expertise.
The Examiner incorporates herein the above 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, written description and 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, rejections.
A “therapeutically effective amount” is a functional property that is dependent upon many different variable parameters, including, but not limited to:
the type of subject human to be treated [parameter 1];
the structure(s) of chimeric antigen receptor [parameter 2];
the type of host cell comprising the chimeric antigen receptor [parameter 3];
the CAR-containing cell dosage administered [parameter 4];
the phenotypic response to be achieved [parameter 5];
the costimulatory domain(s) and signaling domain(s) structure(s) and/or combination(s) and/or subcombination(s) thereof present in the chimeric antigen receptor [parameter 6]; and
the type of cancer that is to be treated [parameter 7].
In Amgen, Inc., v. Sanofi (872 F.3d 1367 (2017)
At 1375, [T]he use of post-priority-date evidence to show that a patent does not disclose a representative number of species of a claimed genus is proper.
At 1377, [W]e questioned the propriety of the "newly characterized antigen" test and concluded that instead of "analogizing the antibody-antigen relationship to a `key in a lock,'" it was more apt to analogize it to a lock and "a ring with a million keys on it." Id. at 1352.
An adequate written description must contain enough information about the actual makeup of the claimed products — "a precise definition, such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other materials," which may be present in "functional" terminology "when the art has established a correlation between structure and function." Ariad, 598 F.3d at 1350. But both in this case and in our previous cases, it has been, at the least, hotly disputed that knowledge of the chemical structure of an antigen gives the required kind of structure-identifying information about the corresponding antibodies. See, e.g., J.A. 1241 (549:5-
16) (Appellants' expert Dr. Eck testifying that knowing "that an antibody binds to a particular amino acid on PCSK9 ... does not tell you anything at all about the structure of the antibody"); J.A. 1314 (836:9-11) (Appellees' expert Dr. Petsko being informed of Dr. Eck's testimony and responding that "[m]y opinion is that [he's] right"); Centocor, 636 F.3d at 1352 (analogizing the antibody-antigen relationship as searching for a key "on a ring with a million keys on it") (internal citations and quotation marks omitted).
In the instant case, knowing that the initial VH and VL amino acid sequence of SEQ ID NO’s 27-30 bind to GPC-3 does not tell you anything at all about the structure (amino acid sequences) of the enormously vast genus of about chimeric antigen receptors comprising:
about 8x10^150 structurally and functionally undisclosed scFv VH domain polypeptides of 116 amino acids that are to have the functional property of binding GPC3; and
about 8x10^143 structurally and functionally undisclosed scFv VH domain polypeptides of 110 amino acids that are to have the functional property of binding GPC3,
that necessarily and predictably bind to GPC3.
Knowing that the initial chimeric antigen receptor may further comprise a transmembrane domain, a costimulatory domain, and a signal domain does not tell you anything at all about the structure (amino acid sequences) of the enormously vast genus of chimeric antigen receptors comprising:
about 8x10^150 structurally and functionally undisclosed scFv VH domain polypeptides of 116 amino acids that are to have the functional property of binding GPC3;
about 8x10^143 structurally and functionally undisclosed scFv VH domain polypeptides of 110 amino acids that are to have the functional property of binding GPC3; and
an infinite and/or enormously vast genus of about 3x10^304 and/or 4x10^119 structurally and functionally undisclosed additional elements of the chimeric antigen receptor, e.g. the transmembrane domain, the costimulatory domain(s), and the signal domain(s), and combinations and/or subcombinations thereof.
Applicant’s own work evidences that the GPC-3 chimeric antigen receptors do not function identically, nor achieve the same therapeutic result(s). For example, not all GPC-3 CAR constructs achieved a statistically meaningful prolonged survival of said mice, as evidenced by the amount of survival varying depending upon the other signaling components within the CAR construct, some being essentially identical to negative control (PBS or T cells lacking GPC-3 CAR), e.g. GPC3-4 BZ, GPC3-2 TZ, GPC3-1 TZ, GPC3-1 BZ, and GPC3-2 28BZ (Figure 10).
Applicant is essentially requiring the ordinary artisans to discover for themselves that which Applicant fails to disclose.
In Amgen, Inc., v. Sanofi (U.S. Supreme Court, No. 21-757 (2023))
“Amgen seeks to monopolize an entire class of things defined by their function”.
“The record reflects that this class of antibodies does not include just the 26 that Amgen has described by their amino acid sequence, but a “vast” number of additional antibodies that it has not.”
“It freely admits that it seeks to claim for itself an entire universe of antibodies.”
In the instant case, the record reflects that the claimed class of anti-GPC3 chimeric antigen receptor molecule variants encompasses an enormously vast genus of chimeric antigen receptors comprising:
about 8x10^150 structurally and functionally undisclosed scFv VH domain polypeptides of 116 amino acids that are to have the functional property of binding GPC3;
about 8x10^143 structurally and functionally undisclosed scFv VH domain polypeptides of 110 amino acids that are to have the functional property of binding GPC3; and
an infinite and/or enormously vast genus of about 3x10^304 and/or 4x10^119 structurally and functionally undisclosed additional elements of the chimeric antigen receptor, e.g. the transmembrane domain, the costimulatory domain(s), and the signal domain(s), and combinations and/or subcombinations thereof.
“They leave a scientist forced to engage in painstaking experimentation to see what works. 159 U.S., at 475.
This is not enablement. More nearly, it is “a hunting license”. Brenner v. Manson, 383 U.S. 519, 536 (1966).
“Amgen has failed to enable all that it has claimed, even allowing for a reasonable degree of experimentation”.
While the “roadmap” would produce functional combinations, it would not enable others to make and use the functional combinations; it would instead leave them to “random trial-and-error discovery”.
“Amgen offers persons skilled in the art little more than advice to engage in “trial and error”.
“The more a party claims for itself the more it must enable.”
“Section 112 of the Patent Act reflects Congress’s judg-ment that if an inventor claims a lot, but enables only a lit-tle, the public does not receive its benefit of the bargain. For more than 150 years, this Court has enforced the stat-utory enablement requirement according to its terms. If the Court had not done so in Incandescent Lamp, it might have been writing decisions like Holland Furniture in the dark. Today’s case may involve a new technology, but the legal principle is the same.
Applicant’s working examples are directed to scFv VH and VL amino acid sequences of SEQ ID NO’s: 27-30, and the nine chimeric antigen receptor species comprising the amino acid sequences of SEQ ID NO’s: 3-10 and 25.
However, Applicant’s own work evidences that not all of these GPC-3 chimeric antigen receptors function identically, nor achieve the same therapeutic result(s). For example, not all GPC-3 CAR constructs achieved a statistically meaningful prolonged survival of said mice, as evidenced by the amount of survival varying depending upon the other signaling components within the CAR construct, some being essentially identical to negative control (PBS or T cells lacking GPC-3 CAR), e.g. GPC3-4 BZ, GPC3-2 TZ, GPC3-1 TZ, GPC3-1 BZ, and GPC3-2 28BZ (Figure 10).
Applicant is essentially requiring the ordinary artisans to discover for themselves that which Applicant fails to disclose.
The courts have stated that reasonable correlation must exist between scope of exclusive right to patent application and scope of enablement set forth in patent application. 27 USPQ2d 1662 Exparte Maizel. In the instant case, in view of the lack of guidance, working examples, breadth of the claims, the level of skill in the art and state of the art at the time of the claimed invention was made, it would have required undue experimentation to make and/or use the invention as claimed.
If little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as to how to make and use the invention in order to be enabling. See, e.g., Chiron Corp. v. Genentech Inc., 363 F.3d 1247, 1254, 70 USPQ2d 1321, 1326 (Fed. Cir. 2004) ("Nascent technology, however, must be enabled with a 'specific and useful teaching.' The law requires an enabling disclosure for nascent technology because a person of ordinary skill in the art has little or no knowledge independent from the patentee's instruction. Thus, the public's end of the bargain struck by the patent system is a full enabling disclosure of the claimed technology." (citations omitted)).
Applicant is essentially requiring the ordinary artisans to discover for themselves that which Applicant fails to disclose.
As In re Gardner, Roe and Willey, 427 F.2d 786,789 (C.C.P.A. 1970), the skilled artisan might eventually find out how to use the invention after “a great deal of work”. In the case of In re Gardner, Roe and Willey, the invention was a compound which the inventor claimed to have antidepressant activity, but was not enabled because the inventor failed to disclose how to use the invention based on insufficient disclosure of effective drug dosage. The court held that “the law requires that the disclosure in the application shall inform them how to use, not how to find out how to use for themselves”.
Perrin (Make Mouse Studies Work, Nature (507): 423-425, 2014) taught that the series of clinical trials for a potential therapy can cost hundreds of millions of dollars. The human costs are even greater (pg 423, col. 1). For example, while 12 clinical trials were tested for the treatment of ALS, all but one failed in the clinic (pg 423, col. 2). Experiments necessary in preclinical animal models to characterize new drugs or therapeutic compounds are expensive, time-consuming, and will not, in themselves, lead to new treatments. But without this upfront investment, financial resources for clinical trials are being wasted and [human] lives are being lost (pg 424, col. 1). Animal models are highly variable, and require a large number of animals per test group. Before assessing a drug’s efficacy, researchers should investigate what dose animals can tolerate, whether the drug reaches the relevant tissue at the required dose and how quickly the drug is metabolized or degraded by the body. We estimate that it takes about $30,000 and 6–9 months to characterize the toxicity of a molecule and assess whether enough reaches the relevant tissue and has a sufficient half-life at the target to be potentially effective. If those results are promising, then experiments to test whether a drug can extend an animal’s survival are warranted — this will cost about $100,000 per dose and take around 12 months. At least three doses of the molecule should be tested; this will help to establish that any drug responses are real and suggest what a reasonable dosing level might be. Thus, even assuming the model has been adequately characterized, an investment of $330,000 is necessary just to determine whether a single drug has reasonable potential to treat disease in humans. It could take thousands of patients, several years and hundreds of millions of dollars to move a drug through the clinical development process. The investment required in time and funds is far beyond what any one lab should be expected to do. (pg 425, col.s 2-3). The human costs are even greater: patients with progressive terminal illnesses may have just one shot at an unproven but promising treatment. Clinical trials typically require patients to commit to year or more of treatment, during which they are precluded from pursuing other experimental options (pg 423, col.2 1-3).
Greenberg (Gene Therapy for heart failure, Trends in Cardiovascular Medicine 27: 216-222, 2017) is considered relevant prior art for taught that despite success in experimental animal models, translating gene transfer strategies from the laboratory to the clinic remains at an early stage (Abstract). The success of gene therapy depends on a variety of factors that will ultimately determine the level of transgene expression within the targeted cells. These factors include the vector used for delivery, the method and conditions of delivery of the vector to the [target tissue], the dose that is given and interactions between the host and the vector that alter the efficiency of transfection of [target] cells (e.g. pg 217, col. 1). Failure of therapeutic results may arise because the vector DNA levels were at the lower end of the threshold for dose-response curves in pharmacology studies, and/or only a small proportion of target cells were expressing the therapeutic transgene (e.g. pg 220, col. 1). Although the use of AAVs for gene therapy is appealing, additional information about the best strain of AAVs to use in human patients is needed. Experience indicates that there is a need to carefully consider the dose of the gene therapy vector; however, this has proved to be difficult in early phase developmental studies due to the complexity and cost of such studies (e.g. pg 221, col. 1).
Maguire et al (Viral vectors for gene delivery to the inner ear, Hearing Research 394: e107927, 13 pages, doi.org/10.1016/j.heares.2020.107927, 2020) is considered relevant post-filing art for taught that despite the progress with AAV vectors in the inner ear, little is known regarding the mechanism of transduction of specific cells by AAV within the cochlea (e.g. pg 2, col. 2). There are limitations to what experiments in mice can tell us about the true translation potential of a new therapeutic (e.g. pg 8, col. 2), e.g. species-related physiological differences between mice and humans (e.g. pg 9, col. 1). The AAV dosage is a significant factor in achieving transduction of the target cell, as insufficient dosage may achieve no transduction of the target cells (e.g. pg 9, col. 2).
Ferdowsian et al (Primates in Medical Research: A Matter of Convenience, not Sound Science, The Hastings Center, www.thehastingscenter.org/primates-in-medical-research-convenience-not-sound-science/; July 8, 2022; last visited September 27, 2024) is considered relevant art for having taught that, “Today, unlike in the 17th century, scientists easily recognize the truth in the saying “mice lie and monkeys exaggerate,” which points to a well-known problem in biomedical research: using nonhuman primates and other animals in research fails more often than it succeeds.”
Tobias (Mouse Study Used in Research, Multiple Sclerosis News Today, multiplesclerosisnewstoday.com/news-posts/2023/09/08/lets-not-get-overexcited-about-any-mice-study-used-research/; September 8, 2023; last visited September 27, 2024) s considered relevant art for having taught that, “Mice exaggerate and monkeys lie, some researchers jokingly say. (Or is it the other way around?)” The odds of an experimental treatment making it from mouse or monkey to human are very low. Less than 8% of cancer treatments make it from animal studies into a clinical setting, where they’re tested on people, and only 10% of the medications in those clinical trials make it through to government approval. No wonder some researchers joke about mice and monkeys lying and exaggerating.
Accordingly, the specification fails to provide any guidance as to how an artisan would have dealt with the art-recognized limitations commensurate with the scope of the claimed invention and therefore, limiting the claimed invention to a method of inhibiting tumor growth, inducing tumor regression, and/or prolonging survival in a mouse subject suffering from a GPC3-expressing cancer, the method comprising the step(s) of:
administering to said mouse subject a pharmaceutical composition comprising at least 4x10^6 T cells expressing a chimeric antigen receptor comprising a transmembrane domain, a costimulatory domain, an intracellular signaling domain, and the GPC3 antigen-binding domain amino acid sequences of SEQ ID NO: 1 and SEQ ID NO:2, is proper.
MPEP 2163 - 35 U.S.C. 112(a) and the first paragraph of pre-AIA 35 U.S.C. 112 require that the “specification shall contain a written description of the invention ....” This requirement is separate and distinct from the enablement requirement. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010) (en banc)
Dependent claims are included in the basis of the rejection because they do not correct the primary deficiencies of the independent claim(s).
Response to Arguments
Applicant argues that the specification demonstrates that T cells expressing the GPC3-1 and GPC3-2 CAR constructs display cytotoxicity against GPC3-expressing human-derived cancer cells in a mouse tumor xenograft model, thereby prolonging the survival of said mice (e.g. Examples 4-5). Thus, under In re Brana, this is sufficient to establish the claimed method has utility.
Applicant’s argument(s) has been fully considered, but is not persuasive.
As a first matter, Applicant’s secondary consideration(s) is/are directed to the GPC3-1 and GPC3-2 CAR constructs. However, as discussed above, one of ordinary skill in the art would immediately recognize that instant independent Claim 29 is vastly broader in scope to the two species of GPC3-1 and GPC3-2 CAR constructs because it encompasses an enormously vast genus of chimeric antigen receptors comprising:
about 8x10^150 structurally and functionally undisclosed scFv VH domain polypeptides of 116 amino acids that are to have the functional property of binding GPC3;
about 8x10^143 structurally and functionally undisclosed scFv VH domain polypeptides of 110 amino acids that are to have the functional property of binding GPC3; and
an infinite and/or enormously vast genus of about 3x10^304 and/or 4x10^119 structurally and functionally undisclosed additional elements of the chimeric antigen receptor, e.g. the transmembrane domain, the costimulatory domain(s), and the signal domain(s), and combinations and/or subcombinations thereof.
As a second matter, Applicant’s secondary consideration(s) is/are directed to T cells expressing the GPC3-1 and GPC3-2 CAR constructs. However, as discussed above, instant independent Claim 29 is vastly broader in scope to the single species of T cells because it encompasses an enormous genus of autologous human host cells, e.g. non-immune cell types, including fibroblast, muscle, endothelial, pancreatic, bladder, kidney, lung, and/or neural cells, and a genus of immune cell types, including dendritic, macrophage, B or T cells, expressing the the an enormously vast genus of chimeric antigen receptors comprising:
about 8x10^150 structurally and functionally undisclosed scFv VH domain polypeptides of 116 amino acids that are to have the functional property of binding GPC3;
about 8x10^143 structurally and functionally undisclosed scFv VH domain polypeptides of 110 amino acids that are to have the functional property of binding GPC3; and
an infinite and/or enormously vast genus of about 3x10^304 and/or 4x10^119 structurally and functionally undisclosed additional elements of the chimeric antigen receptor, e.g. the transmembrane domain, the costimulatory domain(s), and the signal domain(s), and combinations and/or subcombinations thereof.
As a third matter, Applicant’s secondary consideration(s) is/are directed to the administration of a dosage of 4x10^6 T cells expressing the GPC3-1 and GPC3-2 CAR constructs, whereby the therapeutic effect of the GPC3-2 construct was not the same as the GPC3-1 construct, e.g. “were not tolerated at an equivalent in vivo dose” [0164]. GPC3-3 and GPC3-4 constructs did not prolong survival to the same extent as GPC3-1 and GPC3-2 constructs [0166]. Further still, Applicant’s own work evidences that the GPC-3 chimeric antigen receptors do not function identically, nor achieve the same therapeutic result(s). For example, not all GPC-3 CAR constructs achieved a statistically meaningful prolonged survival of said mice, as evidenced by the amount of survival varying depending upon the other signaling components within the CAR construct, some being essentially identical to negative control (PBS or T cells lacking GPC-3 CAR), e.g. GPC3-4 BZ, GPC3-2 TZ, GPC3-1 TZ, GPC3-1 BZ, and GPC3-2 28BZ (Figure 10).
However, as discussed above, one of ordinary skill in the art would immediately recognize that instant independent Claim 29 is vastly broader in scope to the single species of dosage(s) and administration regimen(s) of the mouse tumor xenograft model because it encompasses an enormous genus of autologous human host cells, e.g. non-immune cell types, including fibroblast, muscle, endothelial, pancreatic, bladder, kidney, lung, and/or neural cells, and a genus of immune cell types, including dendritic, macrophage, B or T cells, expressing the an enormously vast genus of chimeric antigen receptors comprising:
about 8x10^150 structurally and functionally undisclosed scFv VH domain polypeptides of 116 amino acids that are to have the functional property of binding GPC3;
about 8x10^143 structurally and functionally undisclosed scFv VH domain polypeptides of 110 amino acids that are to have the functional property of binding GPC3; and
an infinite and/or enormously vast genus of about 3x10^304 and/or 4x10^119 structurally and functionally undisclosed additional elements of the chimeric antigen receptor, e.g. the transmembrane domain, the costimulatory domain(s), and the signal domain(s), and combinations and/or subcombinations thereof, whereby not all of said GPC-3 CAR constructs necessarily and predictably achieved a real-world, clinically meaningful, and statistically significant increase in prolonged survival.
As a fourth matter, the Examiner has not rejected the claims for lack of utility.
Applicant’s own work evidences that the GPC-3 chimeric antigen receptors do not function identically, nor achieve the same therapeutic result(s). For example, not all GPC-3 CAR constructs achieved a statistically meaningful prolonged survival of said mice, as evidenced by the amount of survival varying depending upon the other signaling components within the CAR construct, some being essentially identical to negative control (PBS or T cells lacking GPC-3 CAR), e.g. GPC3-4 BZ, GPC3-2 TZ, GPC3-1 TZ, GPC3-1 BZ, and GPC3-2 28BZ (Figure 10).
To the extent Applicant argues that in the context of pharmaceutical inventions, necessarily includes the expectation of further research and development, Applicant is essentially requiring the ordinary artisans to engage in a research program to discover for themselves that which Applicant fails to disclose.
“They leave a scientist forced to engage in painstaking experimentation to see what works. 159 U.S., at 475.
This is not enablement. More nearly, it is “a hunting license”. Brenner v. Manson, 383 U.S. 519, 536 (1966).
“Amgen has failed to enable all that it has claimed, even allowing for a reasonable degree of experimentation”.
While the “roadmap” would produce functional combinations, it would not enable others to make and use the functional combinations; it would instead leave them to “random trial-and-error discovery”.
“Amgen offers persons skilled in the art little more than advice to engage in “trial and error”.
“The more a party claims for itself the more it must enable.”
“Section 112 of the Patent Act reflects Congress’s judg-ment that if an inventor claims a lot, but enables only a lit-tle, the public does not receive its benefit of the bargain. For more than 150 years, this Court has enforced the stat-utory enablement requirement according to its terms. If the Court had not done so in Incandescent Lamp, it might have been writing decisions like Holland Furniture in the dark. Today’s case may involve a new technology, but the legal principle is the same.
The courts have stated that reasonable correlation must exist between scope of exclusive right to patent application and scope of enablement set forth in patent application. 27 USPQ2d 1662 Exparte Maizel. In the instant case, in view of the lack of guidance, working examples, breadth of the claims, the level of skill in the art and state of the art at the time of the claimed invention was made, it would have required undue experimentation to make and/or use the invention as claimed.
If little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as to how to make and use the invention in order to be enabling. See, e.g., Chiron Corp. v. Genentech Inc., 363 F.3d 1247, 1254, 70 USPQ2d 1321, 1326 (Fed. Cir. 2004) ("Nascent technology, however, must be enabled with a 'specific and useful teaching.' The law requires an enabling disclosure for nascent technology because a person of ordinary skill in the art has little or no knowledge independent from the patentee's instruction. Thus, the public's end of the bargain struck by the patent system is a full enabling disclosure of the claimed technology." (citations omitted)).
As discussed above, the independent claim encompasses an enormous genus of structurally unrecited and undisclosed treatment regimens, dosages, and modalities comprising an enormous genus of autologous human host cells, e.g. non-immune cell types, including fibroblast, muscle, endothelial, pancreatic, bladder, kidney, lung, and/or neural cells, and a genus of immune cell types, including dendritic, macrophage, B or T cells, expressing the enormously vast genus of chimeric antigen receptors comprising:
about 8x10^150 structurally and functionally undisclosed scFv VH domain polypeptides of 116 amino acids that are to have the functional property of binding GPC3;
about 8x10^143 structurally and functionally undisclosed scFv VH domain polypeptides of 110 amino acids that are to have the functional property of binding GPC3; and
an infinite and/or enormously vast genus of about 3x10^304 and/or 4x10^119 structurally and functionally undisclosed additional elements of the chimeric antigen receptor, e.g. the transmembrane domain, the costimulatory domain(s), and the signal domain(s), and combinations and/or subcombinations thereof whereby not all of said GPC-3 CAR constructs necessarily and predictably achieved a real-world, clinically meaningful, and statistically significant increase in prolonged survival for the enormously vast genus of etiologically and pathologically distinct cancers in humans.
Applicant is essentially requiring the ordinary artisans to discover for themselves that which Applicant fails to disclose.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
6. Claims 29 and 32-36 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception without significantly more. Claim 29 recites a method of treating a human subject suffering from cancer, the method comprising the step of administering to said human subject an effective amount of autologous cells expressing an anti-GPC3 chimeric antigen receptor.
The Examiner incorporates herein the above 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, and 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, rejections.
With respect to Step 1, the claim is directed to a process, which is a statutory category of invention (Step 1: YES).
With respect to Step 2A, prong one, the judicial exception, the claims are directed to administering to said human subject an effective amount of autologous cells expressing an anti-GPC3 chimeric antigen receptor, whereby the step of “effective amount” is considered an abstract idea or mental thought performed by the artisan, and thus directed to a judicial exception (Step 2A, prong one: YES).
As discussed above, the claims encompass an enormously vast genus of chimeric antigen receptors comprising:
about 8x10^150 structurally and functionally undisclosed scFv VH domain polypeptides of 116 amino acids that are to have the functional property of binding GPC3;
about 8x10^143 structurally and functionally undisclosed scFv VH domain polypeptides of 110 amino acids that are to have the functional property of binding GPC3; and
an infinite and/or enormously vast genus of about 3x10^304 and/or 4x10^119 structurally and functionally undisclosed additional elements of the chimeric antigen receptor, e.g. the transmembrane domain, the costimulatory domain(s), and the signal domain(s), and combinations and/or subcombinations thereof.
Those of ordinary skill in the art immediately recognize that Applicant simply does not possess the enormously vast genus of chimeric antigen receptors comprising:
about 8x10^150 structurally and functionally undisclosed scFv VH domain polypeptides of 116 amino acids that are to have the functional property of binding GPC3;
about 8x10^143 structurally and functionally undisclosed scFv VH domain polypeptides of 110 amino acids that are to have the functional property of binding GPC3; and
an infinite and/or enormously vast genus of about 3x10^304 and/or 4x10^119 structurally and functionally undisclosed additional elements of the chimeric antigen receptor, e.g. the transmembrane domain, the costimulatory domain(s), and the signal domain(s), and combinations and/or subcombinations thereof.
Thus, the claimed genus of anti-GPC3 chimeric antigen receptors, recited at a high level of generality, is considered to be abstract thought.
Rather, only the two species of GPC3-1 and GPC3-2 scFv antigen-binding domain amino acid sequences, SEQ ID NO: 1 and SEQ ID NO:2, respectively, encoded by the nucleotide sequences of SEQ ID NO:33 and SEQ ID NO:34, respectively, are disclosed.
As discussed above, the claims are broad for encompassing an enormous genus of structurally and functionally different autologous human host cells, e.g. non-immune cell types, including fibroblast, muscle, endothelial, pancreatic, bladder, kidney, lung, and/or neural cells, and a genus of immune cell types, including dendritic, macrophage, B or T cells, comprising the an enormously vast genus of chimeric antigen receptors comprising:
about 8x10^150 structurally and functionally undisclosed scFv VH domain polypeptides of 116 amino acids that are to have the functional property of binding GPC3;
about 8x10^143 structurally and functionally undisclosed scFv VH domain polypeptides of 110 amino acids that are to have the functional property of binding GPC3; and
an infinite and/or enormously vast genus of about 3x10^304 and/or 4x10^119 structurally and functionally undisclosed additional elements of the chimeric antigen receptor, e.g. the transmembrane domain, the costimulatory domain(s), and the signal domain(s), and combinations and/or subcombinations thereof.
Those of ordinary skill in the art immediately recognize that Applicant simply does not possess the therapeutically effective amount of non-immune cell types, including fibroblast, muscle, endothelial, pancreatic, bladder, kidney, lung, and/or neural cells, nor a genus of immune cell types, including dendritic, macrophage, or B cells expressing the an enormously vast genus of chimeric antigen receptors comprising:
about 8x10^150 structurally and functionally undisclosed scFv VH domain polypeptides of 116 amino acids that are to have the functional property of binding GPC3;
about 8x10^143 structurally and functionally undisclosed scFv VH domain polypeptides of 110 amino acids that are to have the functional property of binding GPC3; and
an infinite and/or enormously vast genus of about 3x10^304 and/or 4x10^119 structurally and functionally undisclosed additional elements of the chimeric antigen receptor, e.g. the transmembrane domain, the costimulatory domain(s), and the signal domain(s), and combinations and/or subcombinations thereof.
Thus:
the claimed genus of autologous human host cells, recited at a high level of generality; and
the claimed genus of anti-GPC3 chimeric antigen receptors, also recited at a high level of generality,
is/are considered to be abstract thought.
Rather, the only GPC3 CAR cell therapy reduced to practice is a T cell immunotherapy (e.g. Example 4, [0161]; Example 5, [0169]).
As discussed above, the phrase “prolongs survival of the human subject” in Claim 29 is a relative term which renders the claim indefinite. The phrase “prolongs survival of the human subject” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
A claim may be rendered indefinite by reference to an object that is variable. (MPEP §2173.05(b)).
The breadth of the claims encompasses an enormously vast genus of etiologically and pathologically distinct cancers, including, but not limited to NSCLC, advanced solid malignancies, biliary tract neoplasms, bladder cancer, colorectal cancer, diffuse large b-cell lymphoma, esophageal neoplasms, esophageal squamous cell carcinoma, extensive stage small cell lung cancer, gastric adenocarcinoma, gastric cancer, gastroesophageal junction cancer, head and neck cancer, head and neck squamous cell carcinoma, hepatocellular carcinoma, Hodgkin lymphoma, lung cancer, melanoma, mesothelioma, metastatic clear cell renal carcinoma, metastatic melanoma, metastatic non-cutaneous melanoma, multiple myeloma, nasopharyngeal neoplasms, non-Hodgkin lymphoma, ovarian cancer, fallopian tube cancer, peritoneal neoplasms, pleural mesothelioma, prostatic neoplasms, recurrent or metastatic PD-Ll positive or negative SCCHN, recurrent squamous cell lung cancer, renal cell cancer, renal cell carcinoma, SCCHN, hypo pharyngeal squamous cell carcinoma, laryngeal squamous cell carcinoma, small cell lung cancer, squamous cell carcinoma of the head and neck, squamous cell lung carcinoma, TNBC, transitional cell carcinoma, unresectable or metastatic melanoma, urothelial cancer, and urothelial carcinoma [0123].
A claim may be rendered indefinite by reference to an object that is variable. (MPEP §2173.05(b)). The breadth of the claims encompasses an enormously vast genus of structurally and functionally distinct CAR cell therapy compositions and administration regimens. The specification discloses the CAR cell therapy regimen may be administered alone, or with additional therapeutic agents, such as cytokines (disclosed at a high level of generality), anticancer antibodies, chemotherapeutic agents, and/or additional cell types (disclosed at a high level of generality) [0125, 127].
A claim may be rendered indefinite by reference to an object that is variable. (MPEP §2173.05(b)). The breadth of the claims encompasses an enormously vast genus of temporal variable as to when the GPC-CAR cell therapy dosage and regimen is/are to be administered, from which ‘prolong survival’ is to be determined. For example, the GPC-CAR cell therapy dosage and regimen is/are administered in early stage diagnosis, in the absence of other cancer therapy treatments, after failure of first-line cancer therapy, late stage cancer disease, relapse/recurring aggressive cancer disease, etc… The GPC-CAR cell therapy dosage and regimen is/are administered once, twice, more than three times, more than five times, etc…
Those of ordinary skill in the art immediately recognize that Applicant simply does not possess the therapeutically effective amount of non-immune cell types, including fibroblast, muscle, endothelial, pancreatic, bladder, kidney, lung, and/or neural cells, nor a genus of immune cell types, including dendritic, macrophage, or B cells expressing the enormously vast genus of chimeric antigen receptors comprising:
about 8x10^150 structurally and functionally undisclosed scFv VH domain polypeptides of 116 amino acids that are to have the functional property of binding GPC3;
about 8x10^143 structurally and functionally undisclosed scFv VH domain polypeptides of 110 amino acids that are to have the functional property of binding GPC3; and
an infinite and/or enormously vast genus of about 3x10^304 and/or 4x10^119 structurally and functionally undisclosed additional elements of the chimeric antigen receptor, e.g. the transmembrane domain, the costimulatory domain(s), and the signal domain(s), and combinations and/or subcombinations thereof, to necessarily and predictably achieve a real-world, statistically and clinically meaningful prolongation of the survival of the human subjects suffering from the enormously vast genus of etiologically and pathologically distinct cancers, via the enormous genus of structurally and functionally distinct CAR cell therapy compositions and administration regimens, whereby the CAR cell therapy regimen may be administered alone, or with additional therapeutic agents, including GPC-CAR cell therapy dosages and regimens is/are administered once, twice, more than three times, more than five times, etc…
Thus:
the claimed genus of cancers to be treated, recited at a high level of generality;
via administration of “an effective amount”, also recited at a high level of generality;
via an enormously vast genus of stages of cancer disease, also recited at a high level of generality;
via an enormously vast genus of treatment modalities and regimens, also recited at a high level of generality;
the claimed genus of autologous human host cells, recited at a high level of generality; and
the claimed genus of anti-GPC3 chimeric antigen receptors, also recited at a high level of generality,
is/are considered to be abstract thought.
A claim may be rendered indefinite by reference to an object that is variable. (MPEP §2173.05(b)). The breadth of the claims encompasses an enormously vast genus of anti-TNFalpha antibody dosages and regimens that is/are to be administered.
The specification discloses a working example of administering 100ug of anti-human TNFalpha antibody to mouse subjects (e.g. [0188]), which abolished the efficacy of a GPC3-1-containing CAR [0190].
Norelli et al (Clinical pharmacology of CAR-T cells: Linking cellular pharmacodynamics to pharmacokinetics and antitumor effects, Biochimica et Biophys. Acta 1865: 90-100, 2016; of record) is considered relevant prior art for having taught the step of administering anti-TNFalpha antibodies to those subjects who are receiving CAR T therapy for the treatment of cancer (e.g. pg 97, col. 2) because those of ordinary skill in the art previously recognized that a common and potentially severe side-effect of CAR T cell therapy is cytokine release syndrome (CRS), which often leads to end-stage multi-organ insufficiency, and that attempts to control CRS include the use of anti-TNFalpha antibodies. However, most such attempts have been largely ineffective.
Thus:
the claimed genus of cancers to be treated, recited at a high level of generality;
via administration of “an effective amount”, also recited at a high level of generality;
via an enormously vast genus of stages of cancer disease, also recited at a high level of generality;
via an enormously vast genus of treatment modalities and regimens, also recited at a high level of generality;
the claimed genus of autologous human host cells, recited at a high level of generality;
the claimed genus of anti-GPC3 chimeric antigen receptors, also recited at a high level of generality; and
the claimed genus of anti-TNFalpha antibody dosages and regimens that is/are to be administered, also recited at a high level of generality,
is/are considered to be abstract thought.
As discussed above, those of ordinary skill in the art have long-recognized that each human cancer patient responds differently to their type of cancer and cancer treatment modalities. The ordinary artisan immediately recognizes that one simply cannot know how long the human cancer subject will survive in the absence of the enormous genus of autologous human host cells, e.g. non-immune cell types, including fibroblast, muscle, endothelial, pancreatic, bladder, kidney, lung, and/or neural cells, and a genus of immune cell types, including dendritic, macrophage, B or T cells, expressing the enormously vast genus of chimeric antigen receptors comprising:
about 8x10^150 structurally and functionally undisclosed scFv VH domain polypeptides of 116 amino acids that are to have the functional property of binding GPC3;
about 8x10^143 structurally and functionally undisclosed scFv VH domain polypeptides of 110 amino acids that are to have the functional property of binding GPC3; and
an infinite and/or enormously vast genus of about 3x10^304 and/or 4x10^119 structurally and functionally undisclosed additional elements of the chimeric antigen receptor, e.g. the transmembrane domain, the costimulatory domain(s), and the signal domain(s), and combinations and/or subcombinations thereof, from which to compare ‘prolonged survival’ upon treatment, because it is the same human subject. One simply cannot go back in time after the human subject has died from their cancer, and then decide when during their cancer disease, and by what dosage and administration regimen, the CAR cell therapy is to be performed on the human subject thereby necessarily and predictably prolonging their survival, as such violates the natural law of temporal mechanics, as is understood by modern society. One simply cannot a priori know the future, as such violates the natural law of temporal mechanics, as is understood by modern society.
Thus, here too, the step of determining whether or not a patient having cancer has or has not achieved prolonged survival is an abstract thought, e.g. thinking about the results of the CAR cell therapy, and thus knowing the corresponding “effective amount” is also an abstract thought.
With respect to Step 2A, prong two, the claims do not recite additional elements that integrate the judicial exception into a practical application.
The claimed genus of cancers to be treated, recited at a high level of generality;
via administration of “an effective amount”, also recited at a high level of generality;
via an enormously vast genus of stages of cancer disease, also recited at a high level of generality;
via an enormously vast genus of treatment modalities and regimens, also recited at a high level of generality;
the claimed genus of autologous human host cells, recited at a high level of generality; and
the claimed genus of anti-GPC3 chimeric antigen receptors, also recited at a high level of generality,
is/are considered to be equivalent to “apply the exception”, generally linking the use of the judicial exception to a particular technological environment or field of use.
Those of ordinary skill in the art immediately recognize that different cancer patients are treated differently based on their specific type of cancer, e.g. brain cancer vs prostate cancer vs breast cancer vs colon cancer, etc…
The claims do not integrate the judicial exception into a practical application (Step 2A, prong two: NO).
With respect to Step 2B, the inventive concept is the creation of only two species of GPC3-1 and GPC3-2 scFv antigen-binding domain amino acid sequences, SEQ ID NO: 1 and SEQ ID NO:2, respectively, encoded by the nucleotide sequences of SEQ ID NO:33 and SEQ ID NO:34, respectively, expressed by T cells.
While it is clear that Applicant has treated mouse subjects suffering from hepatocellular carcinoma with said GPC3 CAR T cells (e.g. Examples 4-5), instant claims are far broader in scope to Applicant’s actual invention.
Thus, the claimed genus of cancers to be treated, recited at a high level of generality;
via administration of “an effective amount”, also recited at a high level of generality;
via an enormously vast genus of stages of cancer disease, also recited at a high level of generality;
via an enormously vast genus of treatment modalities and regimens, also recited at a high level of generality;
the claimed genus of autologous human host cells, recited at a high level of generality; and
the claimed genus of anti-GPC3 chimeric antigen receptors, also recited at a high level of generality,
is/are considered to be equivalent to “apply the exception”, generally linking the use of the judicial exception to a particular technological environment or field of use.
Thus, the claims is/are not considered to recite additional elements that amount to significantly more than the judicial exception itself (Step 2B: NO).
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.
7. Claims 1, 5-20, 22-27, 29, and 32-36 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 15-24 of U.S. Patent No. 12,264,190.
Although the claims at issue are not identical, they are not patentably distinct from each other.
‘190 claims a host cell comprising anti-GPC3 chimeric antigen receptor comprising a VH domain comprising SEQ ID NO:27 and a VL domain comprising SEQ ID NO:28,
wherein the anti-GPC3 antigen binding domain is an scFv comprising the amino acid sequence of SEQ ID NO:1,
wherein the anti-GPC3 chimeric antigen receptor comprises the amino acid sequence of SEQ ID NO:25 or SEQ ID NO:47, and
wherein the host cell is a T, NK, CTL, or a Treg cell.
‘190 SEQ ID NO:1, 25, and 47 comprise the amino acid sequences of instantly recited SEQ ID NO:27 and SEQ ID NO:28, and thus also comprise the VH CDR1, CDR2, and CDR3 motifs of SEQ ID NOs: 37, 38, and 39, respectively, and the VL CDR1, CDR2, and CDR3 motifs of SEQ ID NOs: 40, 41, and 42, respectively.
Instant SEQ ID NO:3 differs from ‘190 SEQ ID NO:25 and SEQ ID NO:47 by the presence of a GVHS motif, for example.
However, the specification fails to disclose an element of criticality for the presence and/or absence of the GVHS motif.
The "mere existence of differences between the prior art and an invention does not establish the invention's nonobviousness." Dann v. Johnston, 425 U.S. 219, 230, 189 USPQ 257, 261 (1976). The gap between the prior art and the claimed invention may not be "so great as to render the [claim] nonobvious to one reasonably skilled in the art."Id.
While ‘190 does not claim an isolated nucleic acid encoding said anti-GPC3 chimeric antigen receptor, those of ordinary skill in the art have long-recognized that nucleic acid molecular biology is required to design synthesize and express chimeric antigen receptors from the artisan’s host cell.
Thus, the instant claims are considered to be anticipated by and/or obvious variants of the ‘190 patented claims.
8. Claims 29 and 32-35 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 15-24 of U.S. Patent No. 12,264,190, as applied to Claims 1, 5-20, and 22-27 above, and in further view of Li et al (Redirecting T Cells to Glypican-3 with 4-1BB Zeta Chimeric Antigen Receptors Results in Th1 Polarization and Potent Antitumor Activity, Human Gene Therapy 28(5): 437-448, 2017).
Although the claims at issue are not identical, they are not patentably distinct from each other.
‘190 does not claim a method of treating cancer in a subject comprising the step of administering the CAR-expressing cells to the subject.
However, ‘190 clearly discloses the purpose of the cells expressing the anti-GPC3 chimeric antigen receptor is to treat cancer in a subject (e.g. Title, Abstract), as demonstrated by reductions to practice (Examples 4-5).
Furthermore, Li et al is considered relevant prior art for having taught a method of treating cancer in a mouse subject, the method comprising the step of administering to said mouse a pharmaceutical composition comprising anti-GPC3 CAR T cells (entire paper).
Thus, the instant claims are considered to be obvious variants of the ‘190 patented claims.
9. Claim 36 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 15-24 of U.S. Patent No. 12,264,190 in view of Li et al (2017), as applied to Claims 1, 5-20, 22-27, 29, and 32-36 above, and in further view of Norelli et al (Clinical pharmacology of CAR-T cells: Linking cellular pharmacodynamics to pharmacokinetics and antitumor effects, Biochimica et Biophys. Acta 1865: 90-100, 2016).
Although the claims at issue are not identical, they are not patentably distinct from each other.
‘190 does not claim a method of treating cancer in a subject comprising the step of administering anti-TNFalpha antibodies to the subject.
However, prior to the effective filing date of the instantly claimed invention, Norelli et al is considered relevant prior art for having taught the step of administering anti-TNFalpha antibodies to those subjects who are receiving CAR T therapy for the treatment of cancer (e.g. pg 97, col. 2) because those of ordinary skill in the art previously recognized that a common and potentially severe side-effect of CAR T cell therapy is cytokine release syndrome (CRS), which often leads to end-stage multi-organ insufficiency, and that attempts to control CRS include the use of anti-TNFalpha antibodies.
Conclusion
10. No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KEVIN K. HILL whose telephone number is (571)272-8036. The examiner can normally be reached 12pm-8pm EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Tracy Vivlemore can be reached at 571-272-2914. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
KEVIN K. HILL
Examiner
Art Unit 1638
/KEVIN K HILL/Primary Examiner, Art Unit 1638