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 .
Status of Claims
Claims 1-20 are pending and under examination.
Priority
This application is a continuation of application 17/646,212 filed on December 2, 2021, now U.S. Patent 12,104,178, which is a continuation of:
US 11,6229,340 filed September 2, 2019
PCT/US2018/020704 filed March 2, 2018;
PCT/US2018/020718 filed March 2, 2018;
PCT/US2018/020741 filed March 2, 2018;
PCT/US2018/020755 filed March 2, 2018; and
PCT/US2018/020768 filed March 2, 2018.
Applicant’s claim for the benefit of a prior-filed application provisional applications:
62/555,328 filed on September 7, 2017;
62/555,316 filed on September 7, 2017;
62/542,402 filed on August 8, 2017;
62/542,400 filed on August 8, 2017;
62/484,063 filed on April 11, 2017;
62/484,062 filed on April 11, 2017;
62/484,060 filed on April 11, 2017;
62/484,052 filed on April 11, 2017;
62/484,047 filed on April 11, 2017;
62/466,603 filed on March 3, 2017; and
62/466,601 filed on March 3, 2017
under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 1/10/2025, 03/06/2025, 02/17/2026, 07/02/2026, and 07/27/2026 are considered by the examiner.
Drawings
The drawings filed on 07/29/2024 are accepted.
Specification
The specification filed on 07/29/2024 is accepted.
Claim Interpretation
Claim 1 recites “the destabilizing domain comprises human carbonic anhydrase II (CA2) comprising the amino acid sequence of SEQ ID NO.197 or a region thereof”. Claim 10 recites “wherein the membrane-bound IL15 comprises all or a portion of SEQ ID NO: 718”. The Examiner interprets these recitations to reasonably read upon structures in the prior art in which one or more sequences within (syn. “a region thereof” or ‘a portion”) have 100% identity to some portion of the recited SEQ ID NO, e.g. some fragment or portion of the referenced SEQ ID NO. The present recitations are not interpreted to require the entirety of the recited reference
SEQ ID NOs, nor % identity to measure against the entirety of the recited referenced SEQ ID
NOs.
Claim Rejections - 35 USC § 112(a) – Written Description
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-20 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.
Claim 1 recites a method of treating cancer in a subject, comprising administering to the subject T-cells engineered to express a fusion polypeptide comprising membrane-bound IL15 and a destabilizing domain, wherein the destabilizing domain comprises human carbonic anhydrase II (CA2) comprising the amino acid sequence of SEQ ID NO.197 or a region thereof and one, two, or three mutations relative to the amino acid sequence of SEQ ID NO.197, wherein administration thereby treats the cancer in the subject.
The region of CA2 may comprise amino acids 2 to 260 of SEQ ID NO: 197 or amino acids 1 to 260 of SEQ ID NO: 197 (claims 2 and 3).
The method may further comprise administering to the subject a ligand the destabilizing domain is responsive to (claims 4 and 5). The ligand may be Acetazolamide or Celecoxib (claims 6 and 7).
The T-cells may be autologous or allogeneic to the subject (claims 8 and 9).
The membrane-bound IL-15 may comprise all or a portion of SEQ ID NO: 718 (claim 10). The membrane-bound IL15 may comprise one or more mutations of SEQ ID NO: 718 and maintains one or more functions of full-length membrane-bound IL15 (claim 11.
The membrane-bound IL-15 may further comprise a transmembrane domain (claim 13). The transmembrane domain may be a CD8a transmembrane domain, a CD4 transmembrane domain, a CD 28 transmembrane domain, a CTLA-4 transmembrane domain, a PD-1 transmembrane domain, or a human IgG4 Fc region (claim 14).
The method may further comprise administering to the subject a second anti- cancer therapy in combination with the T-cells (claim 14). The second anti-cancer therapy may be radiation, chemotherapy, a checkpoint inhibitor (e.g., PD-1), or a monoclonal antibody (claims 16-20).
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).
The claims are broad for encompassing an enormous genus of structurally distinct amino acid sequences [structure(s)] having the functional property of being a ‘destabilizing domain’ [function]. Additionally, the mutations are generically recited. The claims are also broad for reciting a genus of ligands.
The specification offers little guidance on these genera. Table 1 discloses CA2 (SEQ ID NO:197) is composed of 260 amino acids. [001152] discloses the breadth of mutations include the addition, substitution, and/or deletion of one or more amino acids. Thus, the claim reasonably encompasses as many as 9x10^47 amino acid substitution variant permutations, in addition to a vast genus of structurally undisclosed variants comprising one or more (essentially unlimited) amino acid additions, in addition to a vast genus of structurally undisclosed variants comprising one, two, or three mutations anywhere within SEQ ID NO:197. Further, the recitation or a region thereof” expands the genus to encompass sequences of any length, as long as they are within the sequence of SEQ ID NO: 197 (e.g., a sequence comprising 10 amino acids reads upon the claim language).
However, the only species disclosed is SEQ ID NO:197 itself.
The specification fails to disclose a first subgenus of SEQ ID NO:197 mutants, and the common core structure thereof, that necessarily and predictably maintain the functional property of being a destabilizing domain, as opposed to a second subgenus of SEQ ID NO:197 mutants that do not maintain the functional property of being a destabilizing domain.
The specification fails to disclose a structure/function nexus between the enormous genus CA2 mutants, and fragments thereof, encompassed by the claims that are necessarily and predictably capable of being a destabilizing domain.
Thus, it is immediately apparent to the ordinary artisan that the instant claims are vastly under-represented by Applicant’s mere single specific embodiment of SEQ ID NO:197.
In kind, claims 10 and 11 are similarly rejected. The claims reasonably encompass as many as 2x10^40 amino acid substitution variant permutations, in addition to a vast genus of structurally undisclosed variants comprising one or more (essentially unlimited) amino acid additions, in addition to a vast genus of structurally undisclosed variants comprising one or more mutations anywhere within SEQ ID NO:718. The only species disclosed is SEQ ID NO:718 itself.
Moreira et al. (Hot spots—A review of the protein–protein interface determinant amino-acid residues, Proteins 68: 803-812, 2007; cited by Examiner in Applicant’s prior application 17/646,212) 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; cited by Examiner in Applicant’s prior application 17/646,212) 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 structurally undisclosed CA2 destabilizing domain variants having the functional property(ies) of binding to an enormous genus of structurally undisclosed targeting ligands, thereby necessarily and predictably destabilizing the IL-15 portion of the fusion protein, and effectively elicit anti-tumor immune responses via the engineered T cell.
Ng et al taught that while multiple sequence alignment of the homologous sequences reveals what positions have been conserved throughout evolutionary time, and these positions are inferred to be important for function (e.g. pg. 63, col. 1), Users should be cautious even with proteins that are judged to be orthologous based on phylogeny. Orthologous genes in different species are derived from a common ancestor, but they may not necessarily have the same function. If function has changed, then amino acids that are important for the function of one protein may not necessarily be important for the function of the ortholog. 2% of disease-causing mutations in human genes are identical to the sequences of their respective mouse orthologs, suggesting that even though these positions have huge phenotypic effects on human health, they have different roles or are no longer important in mice If the orthologs in alignment have slightly different functions, then the positions that differentiate function among orthologs may be incorrectly predicted. (e.g. pg. 68, col. 1). When there are many missense mutations in the gene(s) of interest, assaying all missense mutations, which introduce amino acid changes, can be expensive and time-consuming (e.g. pg. 74, col. 1). Prediction accuracy has gradually improved, but few head-to-head comparisons exist. Moreover, as the number of servers providing AAS prediction increases, it will become increasingly difficult for investigators to interpret the predictions. (e.g. pg. 74, col. 2). Ng et al taught that the error rate of functional annotations in the sequence database is considerable, making it even more difficult to infer correct function from a structural comparison of a new sequence with a sequence database (e.g. Table 1, error rates of about 40% to 60%).
Prediction of protein structure by homology and/or algorithm is notoriously difficult, as one of ordinary skill in the art would immediately understand.
Consequently, the gap between the number of as-yet to be discovered protein sequences of the claimed, but not structurally disclosed, enormously vast genus of CA2 destabilizing domain variants is considered to be tremendous, notoriously difficult, slow, very laborious and time-consuming for the ordinary artisans to determine for themselves that which Applicant has failed to disclose.
Regarding the genus of ligands recited in the claims, the specification offers little guidance on what a ligand can be and how to select an appropriate ligand. Trimethoprim and methotrexate are briefly referred to as examples of ligands for destabilizing domains derived from hDHFR (e.g., [00276]). [00345] teaches the stability control region of Tropomyosin, which controls protein stability comprising a destabilizing mutation L110A and a stabilizing mutation A109L and states “such sequences and be screened for ligands that bind them and regulate their stability”. However, no specific examples of ligands are provided. Further, these ligands are examples for hDHFR destabilizing domains, not CA2 destabilizing domains.
[00347] generically recites “Ligands such as small molecules that are well known to bind candidate proteins can be tested for their regulation in protein responses”. Table 1 teaches examples of proteins and their binding ligands (with acetazolamide and celecoxib the only ligands listed for CA2). However, acetazolamide is not used in any of the working examples, nor a fusion protein comprising CA2 and membrane-bound IL-15, A search of “acetazolamide” and “celecoxib” in the specification only returned recitations in Table 1.
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 structurally undisclosed CA2 destabilizing domain variants having the functional property(ies) of binding to an enormous genus of structurally undisclosed targeting ligands, thereby necessarily and predictably destabilizing the IL-15 portion of the fusion protein, and effectively elicit anti-tumor immune responses via the engineered T cell.
Claim 4 recites the destabilizing domain having the function of being responsive to a ligand.
Claim 12 recites the membrane-bound IL-15 having the function(s) of promotion of natural killer (NK) cell survival; regulation of NK cell and T-cell activation; and proliferation of NK cell development from hematopoietic stem cells.
Either these are inherent property(ies) of (that naturally flows from) the method steps of claim 1, or it is not.
The claim denotes that not all of the structures/method steps of the independent claim are able to achieve the functional property(ies) recited in the dependent claim(s).
To the extent it is not an inherent property (that naturally flows) from the product/method of the independent claim, then something must change. The claim is considered to lack adequate written description for failing to recite the structure that is necessary and sufficient to cause the recited functional language.
The limitations “wherein the destabilizing domain is responsive to a ligand” and “wherein the one or more functions of the full-length membrane- bound IL 15 are selected from the group consisting of promotion of natural killer (NK) cell survival; regulation of NK cell and T-cell activation; and proliferation of NK cell development from hematopoietic stem cells” merely states functional characteristics without providing any indication about how the functional characteristics are provided. The functional characteristics do not follow from (are not inherent property(ies) of) the structure recited in the claim, so it is unclear whether the claim requires some other structure to be added to the composition to provide the functional characteristic. The specification fails to disclose what structural changes to the method is necessary and sufficient to cause the recited survival rate, and thus the ordinary artisan would not know what modification(s) must be made in order to fulfill the instant recitation.
The claims fail to recite, and the specification fails to disclose, a nexus between the method steps/destabilizing domain/membrane-bound IL-15 of claim 1 and the corresponding functional property(ies) of responding to a ligand and promotion of natural killer (NK) cell survival; regulation of NK cell and T-cell activation; and proliferation of NK cell development from hematopoietic stem cells.
For example, are the resulting functional properties dependent upon the mutations in the destabilizing domain? Are certain portions of the membrane-bound IL-15 required to be present? Do the same structure(s) of IL-15 result in all the functions listed in claim 12?
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”).
Claim Rejections - 35 USC § 112(a) – Scope of Enablement
Claims 1-20 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 treating cancer in a subject, comprising
(a) administering to the subject T-cells engineered to express a fusion polypeptide comprising membrane-bound IL15 comprising the amino acid sequence of SEQ ID NO: 718 and a destabilizing domain, wherein the destabilizing domain comprises human carbonic anhydrase II (CA2) comprising the amino acid sequence of SEQ ID NO.197, and
(b) administering to the subject the ligand, wherein the ligand is acetazolamide, thereby treating the cancer in the subject.,
does not reasonably provide enablement for
A method of treating cancer in a subject, comprising administering to the subject T-cells engineered to express a fusion polypeptide comprising membrane-bound IL15 and a destabilizing domain, wherein the destabilizing domain comprises human carbonic anhydrase II (CA2) comprising any region of the amino acid sequence of SEQ ID NO.197 and one, two, or three mutations relative to the amino acid sequence of SEQ ID NO.197, wherein administration thereby treats the cancer in the subject.
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.
The Examiner incorporates herein the analysis discussed above in the 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, written description rejection.
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 Breadth of the Claims and The Nature of the Invention
The claims are directed to a method of treating cancer by administering T cells comprising membrane-bound IL-15 and a destabilizing domain to a subject. The claim specify that the destabilizing domain is derived from human carbonic anhydrase II (CA2), comprises SEQ ID NO: 197.
The claims are broad for reasonably encompassing a large genus of destabilizing domains, mutations present in the destabilizing domain, membrane-bound IL-15 structures, and ligands.
The State of the Prior Art, The Level of One of Ordinary Skill and The Level of Predictability in the Art
The prior art does not teach a fusion protein comprising a membrane-bound IL-15 and a destabilizing domain comprising the carbonic anhydrase 2 (CA2) amino acid sequence of SEQ ID NO:197.
The carbonic anhydrase 2 (CA2) amino acid sequence of SEQ ID NO:197 was previously known in the art. See, for example, GenBank NP_000058 (Carbonic Anhydrase 2 [Homo sapiens], 2015).
The closest prior art teaches a CA9-fusion protein, but not a CA2-fusion protein
Hernandez et al (Clin. Cancer Res. 9:1906-1916, 2003; cited by Examiner in Applicant’s prior application 17/646,212) is considered relevant prior art for having taught a carbonic anhydrase 9 (CA9)-cytokine fusion protein (GMCA-9; Title, Abstract) to induce an immune response in vitro and in vivo. Hernandez et al taught a recombinant adenoviral vector comprising a nucleic acid encoding the GMCA-9 fusion protein (Abstract).
Hernandez et al taught human dendritic cells transduced with a recombinant adenoviral vector comprising a nucleic acid encoding the GMCA-9 fusion protein (Abstract), and thus taught a method of producing a genetically engineered immune cell comprising a recombinant viral vector comprising a nucleic acid encoding the GMCA-9 fusion protein (pg 1908, col. 1, DC Generation and Transduction).
Hernandez et al taught a pharmaceutical composition comprising a pharmaceutically acceptable carrier (PBS, pg 1908, col. 2, Animal Studies) and the genetically modified immune cells comprising the recombinant adenoviral vector comprising a nucleic acid encoding the GMCA-9 fusion protein, said pharmaceutical composition being injected into mice (pg 1910, col. 1).
While Hernandez et al do not teach ipsis verbis that the CA9 comprises a drug-responsive domain (DRD), those of ordinary skill in the art have long-recognized that CA9 naturally comprises a DRD, capable of binding acetazolamide.
However, Hernandez et al differs from the instantly claimed invention because they do not teach the fusion protein is membrane-bound, nor a method of modulating the expression, function, and or level of the cytokine in the genetically modified immune cells using acetazolamide.
Ahlskog et al. (Ahlskog, Julia KJ, et al. "In vivo targeting of tumor-associated carbonic anhydrases using acetazolamide derivatives." Bioorganic & medicinal chemistry letters 19.16 (2009): 4851-4856.; cited by Examiner in Applicant’s prior application 17/017,670) is considered relevant prior art for having taught that carbonic anhydrase 9 (CA9) naturally comprises a drug-responsive domain (DRD), whereby said DRD binds acetazolamide (pg 4852, col. 1, “We used acetazolamide….to inhibit…carbonic anhydrases…including CA9”).
Hoyos et al. (Hoyos, Valentina, et al. "Engineering CD19-specific T lymphocytes with interleukin-15 and a suicide gene to enhance their anti-lymphoma/leukemia effects and safety." Leukemia 24.6 (2010): 1160-1170.; of record in IDS) is considered relevant prior art for having taught a nucleic acid sequence encoding a fusion protein comprising IL-15 operably linked to a drug-responsive domain, to wit, inducible caspase-9 (iC9), such that in the presence of the drug, the genetically modified immune effector cells undergo apoptosis, thereby avoiding uncontrolled growth of the immune effector cells in vivo (pg 1165, col. 1).
The Examiner notes that a cleavable 2A peptide domain separates the iC9 domain from CAR polypeptide, and a cleavable 2A peptide domain separates the CAR polypeptide from the IL-15 polypeptide (Supplemental Figure 1), and thus it is considered that the mature IL-15 polypeptide does not comprise the iC9 polypeptide nor the CAR polypeptide.
Campana et al (WO2015174928A1; cited by Examiner in Applicant’s prior application 17/646,212) is considered relevant prior art for having disclosed nucleic acid molecules encoding membrane-bound IL-15 fusion protein comprising a CD8 transmembrane domain, and expressing the membrane-bound IL-15 fusion protein in human NK immune cells [0020].
Additionally, the prior art teaches using acetazolamide for stabilization, but does not suggest that any stimulus would be effective for this purpose, and explicitly demonstrates that other stimuli would unsuitable.
Inniss et al. (Inniss, Mara C., et al. "Carbonic anhydrase 2-derived drug-responsive domain regulates membrane-bound cytokine expression and function in engineered T cells." Communications Biology 8.1 (2025): 28., Applicant’s work; cited by Examiner in Applicant’s prior application 17/753,594) is considered relevant post-filing art for teaching T cells armored with membrane-bound cytokines using drug-responsive domains (DRDs) developed from human carbonic anhydrase 2 (CA2) for targeting tumors (cancers) (Abstract; Fig. 2h). While CA2 inhibitors and drugs known to have off-target activity on CA2 were also capable of stabilizing CA2-DRDs with varying levels of potency ethoxzolamide is discontinued, celecoxib has insufficient potency, and brinzolamide is approved only for non-systemic usage (pg. 2, “Results”). However, a step of adding the stimulus acetazolamide specifically stabilizes the CA2-DRD (and the cytokine payload) (Abstract; pg. 2, “Results”).
Burga et al. (Burga, Rachel A., et al. "IL-2-independent expansion, persistence, and antitumor activity in TIL expressing regulatable membrane-bound IL-15." Molecular Therapy 33.8 (2025): 3605-3623.; cited by Examiner in Applicant’s prior application 17/753,594) is considered relevant post-filing art for teaching that only FDA-approved acetazolamide is demonstrated as being suitable for regulating the activity of TILs armored with membrane bound IL-15 for antitumor responses (pg. 3, Introduction). The presence of acetazolamide stabilizes the DRD, increasing surface expression of mbIL15, whereas in the absence of ACZ, the DRD is unstable, and the DRD-mbIL15 fusion protein is degraded by the proteasome (pg. 3, Introduction).
Therefore, the state of the art only demonstrates that acetazolamide is suitable stabilizing destabilizing domains comprising CA2 in cellular therapies for treating patients, but does not suggest that any stimulus would be effective for this purpose, and explicitly demonstrates that other stimuli would unsuitable.
Consequently, there is ample reason to conclude that there would be a high degree of unpredictability in using the method with a stimulus other than acetazolamide.
In summary, while the prior art teaches SEQ ID NO: 197 and acetazolamide as a ligand for the destabilizing domain, the art does not teach a fusion protein comprising a membrane-bound IL-15 and a destabilizing domain comprising the carbonic anhydrase 2 (CA2) amino acid sequence of SEQ ID NO:197, nor other ligands that may act as a stabilizer for the fusion protein.
The Existence of Working Examples and The Amount of Direction Provided by the Inventor
The Examiner incorporates herein the analysis discussed above in the 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, written description rejection.
Since the quantity of experimentation required to practice the invention as claimed is undetermined, one of skill in the art would have been unable to practice the invention without engaging in undue trial and error experimentation as presented in the specification over the scope claimed.
The Quantity of Any Necessary Experimentation to Make or Use the Invention
Thus, the quantity of necessary experimentation to make or use the invention as claimed, based upon what is known in the art and what has been disclosed in the specification, will create an undue burden for a person of ordinary skill in the art to necessarily and predictably use the claimed method comprising administering T cells engineered to express a fusion protein comprising a membrane-bound IL-15 and a destabilizing domain comprising the carbonic anhydrase 2 (CA2) amino acid sequence of SEQ ID NO:197 to treat cancer. Additionally, there is an undue burden for a person of ordinary skill in the art to necessarily and predictably use the claimed method with the destabilizing domain being responsive to ligands other than acetazolamide.
In conclusion, the specification fails to provide any guidance as to how an artisan would have dealt with the art-recognized limitations of the claimed method commensurate with the scope of the claimed invention.
Claim Rejections - 35 USC § 112(b)
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.
Claim 5 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 5 recites “The method of claim 4, further comprising administering to the subject the ligand.” As written, it is unclear when in the claimed method the ligand may be administered. For example, is this administration required to take place after administering the engineered T cells? It would be remedial to clarify the order of the method steps. For examination purposes, the method step of claim 5 may take place before, during, or after the method step of claim 1.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 11 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 10 recites wherein the IL15 comprises all or a portion of SEQ ID NO:718.
Claim 11 recites wherein the IL15 comprises one or more mutations of SEQ ID NO:718 and maintains one or more functions of full-length membrane-bound IL15.
It is axiomatic that the limitation “comprises one or mutations of SEQ ID NO:718” does not comprise all of SEQ ID NO:718. It is also axiomatic that a portion of SEQ ID NO:718 is one or more mutations of SEQ ID NO:718. Thus, Claim 11 fails to further limit Claim 10.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-6 and 10-13 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, and 5 of U.S. Patent No. 12,642,792. Although the claims at issue are not identical, they are not patentably distinct from each other because the reference patent is a species of the instant application.
Claims 1-4: reference claim 1 is drawn to a method of treating cancer responsive to regulated IL-1. The method comprises administering a therapeutically effective amount of a cell comprising a nucleic acid molecule comprising a polynucleotide encoding a recombinant protein comprising a drug responsive domain (DRD) operably linked to an IL15 payload, wherein the DRD is derived from human carbonic anhydrase II (CA2) and comprises the amino acid sequence of SEQ ID NO:4 and wherein the IL15 payload is a membrane-bound IL15 polypeptide. The cell is a tumor infiltrating lymphocyte (TIL), a human T cell or a human NK cell. SEQ ID NO: 4 of reference ‘792 shares 99.2% identity with instant SEQ ID NO: 197.
Following administering a cell, a therapeutically effective amount of a stimulus is administered to the subject, wherein the DRD is stabilized by the stimulus to enable expression of the IL15 payload.
Claims 5 and 6: reference claim 1 recites that the stimulus (comparable to the ligand of the instant application) is acetazolamide.
Claims 10 and 11: reference claim 3 recites the membrane-bound IL15 comprising SEQ ID NO: 8. SEQ ID NO: 8 shares 100% identity with instant SEQ ID NO: 718.
Claim 12: as discussed above, claim 12 does not further limit the structure of the claimed method. Therefore, reference claim 1 reads upon the limitations of reference claim 1.
Claim 13: reference claim 5 recites the recombinant protein (IL-15 polypeptide) comprising a transmembrane domain.
Claims 1-3, 5, 6, and 10-13 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 and 5 of U.S. Patent No. 11,08,725. Although the claims at issue are not identical, they are not patentably distinct from each other because the reference patent is a species of the instant application.
Claims 1-3: reference claim 1 is drawn to a product (e.g., a nucleic acid molecule used in the instantly claimed method. SEQ ID NO: 4 of reference ‘725 shares 99.2% identity with instant SEQ ID NO: 197.
Claims 5, 6: reference claim 2 recites a method of modulating the expression, function, and/or level of IL15 in a human T cell, natural killer (NK) cell, or tumor infiltrating lymphocyte (TIL) (e.g., cell of reference claim 18), said method comprising administering acetazolamide to the cell, wherein the acetazolamide is administered in an amount sufficient to modulate the expression, function and/or level of IL15.
Claims 10, 11: reference claim 3 recites the membrane-bound IL15 comprising SEQ ID NO: 8. SEQ ID NO: 8 shares 100% identity with instant SEQ ID NO: 718.
Claim 12: as discussed above, claim 12 does not further limit the structure of the claimed method. Therefore, reference claim 1 reads upon the limitations of reference claim 1.
Claim 13: reference claim 5 recites the recombinant protein (IL-15 polypeptide) comprising a transmembrane domain.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALLISON M JOHNSON whose telephone number is (703)756-1396. The examiner can normally be reached Monday-Friday 9am-5pm.
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ALLISON M. JOHNSON
Examiner
Art Unit 1638
/ALLISON MARIE JOHNSON/ Examiner, Art Unit 1638
/ROBERT M KELLY/ Primary Examiner, Art Unit 1638
