DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims Status
2. The preliminary amendments filed 01/21/2025 are acknowledged. Claims 4-6, 8, 10, 11, 13, 20, 22, 24, 27, 29, 42-45, and 49 are amended. Claims 3, 7, 9, 12, 14-19, 23, 25, 26, 28, 30-41, 46-48, and 50-52 are canceled. Claims 1-2, 4-6, 8, 10-11, 13, 20-22, 24, 27, 29, 42-45, and 49 are pending and under examination.
Information Disclosure Statement
3. The information disclosure statement (IDS) submitted 08/15/2025 and the references cited therein have been considered, unless indicated otherwise.
Specification
4. The use of the term “IncuCyte Zoom” (page 35, example 7), which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks. Please review the specification for other trademarks and appropriate correction is required.
Claim Objections
5. Claims 6 and 42 are objected to because of the following informalities:
Claim 6 is objected to because of the following informality: claim 6 recites “The method claim 1“. Adding “of” between “method” and “claim” will overcome the objection.
Claim 43 is objected to because “uterine cancer” is recited twice in the list of cancers. Deletion of the duplicate recitations will overcome the objection.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
6. Claims 1, 2, 4-6, 8, 10-11, 13, 20-22, 24, 27, 29, 45, and 49 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites “A method of treating a subject in need thereof, comprising administering to the subject a population of modified immune cells…”. The claim does not recite any disease, disorder, or condition to be treated. Because no condition is identified, it cannot be determined what the subject is “in need of, what population of subject within the scope of “in need thereof,” or what is encompassed by “treating”. The metes and bounds of the claim therefore cannot be ascertained, and the claim is indefinite. Dependent claims 2, 4-6, 8, 10-11, 13, 20-22, 24, 27, 29, 45, and 49 do not remedy the deficiency on claim 1, and thus, are included in the rejection.
7. Claim 24 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 24 depends from claim 20 and recites “a fourth gRNA”, “a fourth component of the SAGA complex,” and “wherein the first component of the SAGA complex, the second component of the SAGA complex, the third component of the SAGA complex are different.” Claim 20 introduces only a first and second gRNA and a first and second component of the SAGA complex; a third gRNA and a third component are introduced only in claim 22, from which claim 24 does not depend. Accordingly, “the third component of the saga complex” and “the fourth component of the SAGA complex” lack proper antecedent basis.
The clause “the third component of the SAGA complex are different, and the fourth component of the SAGA complex are different” is further indefinite, as it is grammatically incomplete and fails to specify that against which components are “different”.
8. Claim 27 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 27(vii) recites “exhibit increased phosphor-ATK levels follow stimulation”. The term “phosphor-ATK” has no recognized meaning in the art and cannot be reconciled with the analytes elsewhere in the claim. Thus, the limitation is indefinite and clarification is required.
9. Claim 45 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 45 recites “administering to the subject an additional anticancer agent comprising an immunotherapy, a chemo therapy, a cytokine, a radiation therapy, a surgery, or any combinations thereof”.
The recitation of “a radiation therapy’ and “a surgery” are not “agents” and cannot be “administered” as an anticancer “agent”, which creates inconsistency between the recited genus of “agent” and the step of “administering”. The scope of the claim therefore cannot be determined.
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.
Written Description
10. Claims 1-2, 4-6, 8, 10-11, 13, 20-22, 24, 27, 29, 42-45, and 49 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.”
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the Applicants were in possession of the claimed genus.
The claims are drawn to a method of treating a subject in need thereof, comprising administering to the subject a population of modified immune cells, which comprises one or more modified immune cells having decreased expression of one or more components of the SAGA (Spt-Ada- Gcn5-acetyltransferase) complex, relative to an unmodified immune cell (claim 1); wherein the modified immune cell comprises a nucleic acid encoding a chimeric antigen receptor (CAR) or a nucleic acid encoding a heterologous T cell receptor (TCR); wherein the CAR, the TCR, or both comprise an antigen-binding domain, wherein the antigen-binding domain specifically binds an antigen expressed on the surface of a tumor cell (claim 6); wherein the one or more components of the SAGA complex comprise USP22, TADA1, TADA2b, TAF6L, or any combination thereof (claim 10); wherein the expression of the one or more components of the SAGA complex is inhibited or blocked by contacting the immune cells with (i) a Cas9 protein and a CRISPR-cas system guide RNA (gRNA), (ii) an antisense oligonucleotide, (iii) an siRNA, (iv) an shRNA, (v) a small molecule inhibitor, (vi) a prime editing guide RNA, or (vii) any combination thereof (claim 11).
The specification teaches CRISPR guide RNAs targeting USP22, TADA1, TADA2b, TAF6L, or TRRAP will be contacted with T cells to knock out the SAGA complex. T cells will be transduced with an expression vector encoding a CAR construct (example 3). The specification teaches SAGA-depleted CAR-T, TCR transgenic T cells, and TILs will be administered to human subjects afflicted with a cancer. The specification teaches T cells depleted of SAGA were generated by knockout of various targets: gTADA1 KO, gTADA2b KO, gTAF6L KO. CD107a expression was increased in SAGA depleted T cells lacking expression of USP22 (FIG. 1U), TADA1 (FIG. 1V), TADA2b (FIG. 1W), TAF6L (FIG. 1X), or TRRAP (FIG. lY), as compared to control (wild type; FIG. 1T) cells (example 1). The specification teaches the expression of the one or more components of the SAGA complex is inhibited or blocked by contacting the immune cells with (i) a Cas9 protein and a CRISPR-cas system guide RNA (gRNA), (ii) an antisense oligonucleotide, (iii) an siRNA, (iv) an shRNA, (v) a small molecule inhibitor, (vi) a prime editing guide RNA, or (vii) any combination thereof. In some aspects, the expression of the one or more components of the SAGA complex is inhibited or blocked by contacting the immune cells with a Cas9 protein and a CRISPR-cas system guide RNA (gRNA). In some aspects, the Cas9 protein, the gRNA, or both are expressed from a heterologous expression construct introduced into the immune cell. In some aspects, the gRNA is a single guide RNA (sgRNA) (paragraph 9).
First, independent claim 1 recites administering a population of modified immune cells “having decreased expression of one or more components of the SAGA complex, relative to an unmodified immune cell.” The limitation is defined solely by a functional result of decreasing expression and method of treating, without limitation as to which SAGA complex component is reduced, the specific population being treated, the mechanism or degree of reduction or the identity of the immune cell. Thus, the claims recite a genus defined by function rather than by structure. The specification teaches USP22, TADA1, TADA2b, TAF6L, or TRRAP, however, this is does not appear to describe a representative number of species across the full breadth of “one or more components of the SAGA complex”, nor a structure/function correlation demonstrating possession of the full claim genus; reducing of any and all saga complex components, by an mechanism, to any degree, in any type of immune cell.
Second, claim 6 recites an “antigen-binding domain”, defined entirely by the function of specifically binding a recited antigen without any recited structure (CDRs, variable region domains) for the domain. The specification does not appear to describe a representative number of antigen-binding domains commensurate with the claims function.
Third, claim 11 recites various agents that can inhibit or block the expression of the one or more components of the SAGA complex. The specification fails to describe the structural features common to members of the genus that would allow the skilled artisan to distinguish agents encompassed by the claims from other agents, and disclose any correlation between the structure and function of the agents encompassed by the claims. While the specification teaches that the expression of the one or more components of the SAGA complex is inhibited or blocked by contacting the immune cells with a Cas9 protein and a CRISPR-cas system guide RNA (gRNA), generically stating the type of agent that can inhibit or block one or more components of the SAGA complex is not a description of the agent itself. That is because knowing the broad class to which agents can cause decreased expression of one or more components of the SAGA complex does not provide any information regarding the specific structure that yields the required function(s). Thus, the specification fails to describe how the decreased expression of the SAGA complex occurs. Although those of ordinary skill in the art could prepare the claimed agents, it is the specification itself that must demonstrate possession. “A biomolecule sequence described only by a functional characteristic, without any known or disclosed correlation between that function and the structure of the sequence, normally is not a sufficient identifying characteristic for written description purposes, even when accompanied by a method of obtaining the claimed sequence”. Thus, the specification fails to describe the agents required to practice the claimed method in a manner that reasonably conveys to those skilled in the art that Applicant was in possession of the claimed method.
Disclosing species that directly inhibit some of the 19 subunits of the SAGA complex and species that directly inhibit transcription of SAGA’s subunits via CRISPR-Cas system do not represent the entire genus. The claimed genus encompasses much broader species. Furthermore, the specification does not disclose a representative number of species to describe the genus. The specification clearly sets forth the correlation of decreased expression of one or more components of the SAGA complex and treating a subject. Example 7 in the specification recites in vitro killing of A375 melanoma cancers cells transgenic NYESO-1+ T cells depleted of SAGA targets include gTADA1 KO, gTADA2b KO, and gTAF5L KO. Further tests in vivo demonstrated mice administered gTADA2b KO T NY-ESO 1 TCR+ T cells exhibited decreased melanoma tumor volume. However, the correlation between the aforementioned agent(s) and the corresponding function(s) set forth above do not appear to be clearly present in the breadth of the claims. The claims are generic for treating a subject in need thereof, comprising administering modified immune cells having decreased expression of one or more components of the SAGA complex. Thus, the genus has substantial variation because of the numerous options and combinations permitted. However, the species disclosed are not deemed to be representative of the genus because the few species disclosed do not reflect the variation within the genus. There is no indication in the specification that other species encompassed by the genus that differ from the few species disclosed will have the same functional characteristics and one of skill in the art would not be able to predict the operability of any species other than the ones disclosed. When there is substantial variation within the genus, the specification must describe a sufficient variety of species to reflect the variation within the genus. Thus, the specification does not adequately reflect the structural diversity of the claimed genus, either by the establishment of "a reasonable structure-function correlation or through the disclosure of sufficient number of species that are "representative of the full variety or scope of the genus”. Therefore, the specification provides insufficient written description to support the genus of compositions encompassed by the claim.
Vas- Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that
"applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.)The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing 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.
A description of a genus may be achieved by means of a recitation of a representative number of species falling within the scope of the genus or of a recitation of structural features common to the members of the genus, which features constitute a substantial portion of the genus. Regents of the University of California v. Eli Lilly & Co., 119 F3d 1559,1569, 43 USPQ2d 1398,1406 (Fed. Cir. 1997). In Regents of the University of California v. Eli Lilly (43 USPQ2d 1398-1412), the court held that a generic statement which defines a genus of nucleic acids by only their functional activity does not provide an adequate written description of the genus. The court indicated that, while applicants are not required to disclose every species encompassed by a genus, the description of the genus is achieved by the recitation of a representative number of species falling within the scope of the claimed genus. At section B(l), the court states, "An adequate written description of a DNA ... requires a precise definition, such as by structure, formula, chemical name, or physical properties, not a mere wish or plan for obtaining the claimed chemical invention."
In Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336,1351 (Fed. Cir. 2010), the court held that a "sufficient description of a genus ... requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can 'visualize or recognize' the members of the genus." Ariad, 598 F.3d at 1350. "[A]n adequate written description requires 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." Id. Although "functional claim language can meet the written description requirement when the art has established a correlation between structure and function," "merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genus and showing that one has invented a genus and not just a species." Id.
Furthermore, regardless whether a compound is claimed per se or a method is claimed that entails the use of the compound, the inventor cannot lay claim to that subject matter unless he can provide a description of the compound sufficient to distinguish infringing compounds from non-infringing compounds, or infringing methods from non-infringing methods. Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920-23, 69 USPQ2d 1886,1890-93 (Fed. Cir. 2004).
The specification and claims teaches that such components of the SAGA complex can exhibit decreased expression through contacting the immune cells with (i) a Cas9 protein and a CRISPR-cas system guide RNA (gRNA), (ii) an antisense oligonucleotide, (iii) an siRNA, (iv) an shRNA, (v) a small molecule inhibitor, (vi) a prime editing guide RNA, or (vii) any combination thereof. Thus, the claims broadly encompass an indeterminate number of agents that can caused decreased expression of the SAGA complex. The instant claims thereby encompass many genera of chemical and biological molecules, without any described structure that is required for the molecules to perform the required functions.
Regarding the encompassed proteins, protein chemistry is one of the most unpredictable areas of biotechnology. Consequently, the effects of sequence dissimilarities upon protein structure and function cannot be predicted. Bowie et al. (Science, 1990, 247:1306-1310) teach that an amino acid sequence encodes a message that determines the shape and function of a protein and that it is the ability of these proteins to fold into unique three-dimensional structures that allows them to function and carry out the instructions of the genome and further teaches that the problem of predicting protein structure from sequence data and in turn utilizing predicted structural determinations to ascertain functional aspects of the protein is extremely complex (column 1, page 1306). Bowie et al. further teach that while it is known that many amino acid substitutions are possible in any given protein, the position within the protein's sequence where such amino acid substitutions can be made with a reasonable expectation of maintaining function are limited. Certain positions in the sequence are critical to the three dimensional structure/function relationship and these regions can tolerate only conservative substitutions or no substitutions at all (column 2, page 1306). The sensitivity of proteins to alterations of even a single amino acid in a sequence are exemplified by Burgess et al. (J. Cell Biol. 111:2129-2138, 1990) who teach that replacement of a single lysine reside at position 118 of acidic fibroblast growth factor by glutamic acid led to the substantial loss of heparin binding, receptor binding and biological activity of the protein and by Lazar et al. (Mol. Cell. Biol., 8:1247-1252, 1988) who teach that in transforming growth factor alpha, replacement of aspartic acid at position 47 with alanine or asparagine did not affect biological activity while replacement with serine or glutamic acid sharply reduced the biological activity of the mitogen. These references demonstrate that even a single amino acid substitution will often dramatically affect the biological activity and characteristics of a protein.
Additionally, Bork (Genome Research, 2000, 10:398-400) clearly teaches the pitfalls associated with comparative sequence analysis for predicting protein function because of the known error margins for high-throughput computational methods. Bork specifically teaches that computational sequence analysis is far from perfect, despite the fact that sequencing itself is highly automated and accurate (p. 398, column 1). One of the reasons for the inaccuracy is that the quality of data in public sequence databases is still insufficient. This is particularly true for data on protein function. Protein function is context dependent, and both molecular and cellular aspects have to be considered (p. 398, column 2). Conclusions from the comparison analysis are often stretched with regard to protein products (p. 398, column 3). Further, although gene annotation via sequence database searches is already a routine job, even here the error rate is considerable (p. 399, column 2). Most features predicted with an accuracy of greater than 70% are of structural nature and, at best, only indirectly imply a certain functionality (see legend for table 1, page 399). As more sequences are added and as errors accumulate and propagate it becomes more difficult to infer correct function from the many possibilities revealed by database search (p. 399, paragraph bridging columns 2 and 3). The reference finally cautions that although the current methods seem to capture important features and explain general trends, 30% of those features are missing or predicted wrongly. This has to be kept in mind when processing the results further (p. 400, paragraph bridging cols 1 and 2). Given not only the teachings of Bowie et al., Lazar et al. and Burgess et al. but also the limitations and pitfalls of using computational sequence analysis and the unknown effects of alternative splicing, post translational modification and cellular context on protein function as taught by Bork, the claimed proteins could not be predicted based on sequence identity.
Regarding the encompassed antibodies, the functional characteristics of antibodies, including binding specificity and affinity, are dictated on their structure. Amino acid sequence and conformation of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin. For example, Vajdos et al. (J Mol Biol. 2002 Jul 5;320(2):415-28 at 416) teaches that, “ … Even within the Fv, antigen binding is primarily mediated by the complementarity determining regions (CDRs), six hypervariable loops (three each in the heavy and light chains) which together present a large contiguous surface for potential antigen binding. Aside from the CDRs, the Fv also contains more highly conserved framework segments which connect the CDRs and are mainly involved in supporting the CDR loop conformations, although in some cases, framework residues also contact antigen. As an important step to understanding how a particular antibody functions, it would be very useful to assess the contributions of each CDR side-chain to antigen binding, and in so doing, to produce a functional map of the antigen-binding site." The art shows an unpredictable effect when making single versus multiple changes to any given CDR. For example, Brown et al. (J Immunol. 1996 May; 156(9):3285-91 at 3290 and Tables 1 and 2), describes how the VH CDR2 of a particular antibody was generally tolerant of single amino acid changes, however the antibody lost binding upon introduction of two amino changes in the same region.
Recently, the U.S. Court of Appeals for the Federal Circuit (Federal Circuit) decided Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017), which concerned adequate written description for claims drawn to antibodies. The Federal Circuit explained in Amgen that when an antibody is claimed, 35 U.S.C. § 112(a) requires adequate written description of the antibody itself even when preparation of such an antibody would be routine and conventional. Amgen, 872 F.3d at 1378-79. A key role played by the written description requirement is to prevent "attempts] to preempt the future before it has arrived." Ariad at 1353, (quoting Fiers v. Revel, 984 F.2d at 1171). Upholding a patent drawn to a genus of antibodies that includes members not previously characterized or described could negatively impact the future development of species within the claimed genus of antibodies. In the instant application, neither the art nor the specification provide a sufficient representative number of antibodies or a sufficient structure-function correlation to meet the written description requirements.
Regarding small molecule inhibitors of a particular protein target, the prediction of binding to a target, much less the inhibitory activity, is highly unpredictable. According to Guido et al (Curr Med Chem. 2008; 15(1):37-46), accurately predicting the binding affinity of new drug candidates remains a major challenge in drug discovery (see page 37). There are a vast number of possible compounds that may function as an inhibitor of a cytokine or cytokine receptor, many of which have likely not been discovered. Relying on virtual screening also lends unpredictability to the art regarding identification of molecules that would be capable of the required functions of the instant claims. Guido et al. teach that there are two main complex issues with predicting activity for a small molecule: accurate structural modeling and/or correct prediction of activity (see page 40). As taught by Clark et al (J. Med. Chem., 2014, 57 (12), pp 5023–5038), developing selective JAK inhibitors is difficult. Even when guided by structure, JAK structure-activity relationships has been challenging owing to the similarities of the enzymes (see page 5028). Therefore, it is impossible for one of skill in the art to predict that any particular encompassed small molecule therapeutic would function to inhibit a particular protein, or treat disease.
Regarding nucleic acid based agents, the efficacy of any possible RNA interference therapeutic modality is highly unpredictable. This unpredictability stems from an inability to predict the effects of any particular sequence the expression or function of any target. As taught by Aagaard et al. (Advanced Drug Delivery Reviews 59 (2007) 75-86), the development of RNAi based therapeutics faces several challenges, including the need for controllable or moderate promoter systems and therapeutics that are efficient at low doses (see page 79), the ability of an unpredictable number of sequences to stimulate immune responses, such as type I interferon responses (see page 79), competition with cellular RNAi components (see page 83), the side effect of suppressing off targets (see page 80), and challenging delivery (see page 83). The success of antisense strategies, including anti-RNA and anti-DNA strategies are also highly unpredictable. Warzocha et al. (Leukemia and Lymphoma, 1997; 24(3-4): 267-281) teach that the efficacy of antisense effects varies between different targeted sites of RNA molecules and three dimensional RNA structures (see page 269), while DNA- targeting strategies have numerous problems including a restricted number of DNA sequences that can form triple helices at appropriate positions within genes and the inaccessibility of particular sequences due to histones and other proteins (see page 269). These references demonstrate that variation in RNA or DNA based therapeutics will often dramatically affect the biological activity and characteristics of the intended therapeutic. Given the teachings of Aagaard et al. and Warzocha et al., the claimed RNA and DNA therapeutics could not be predicted based on the targets selected or similarities to the disclosed example therapeutics. Therefore, it is impossible for one of skill in the art to predict that any particular encompassed RNA or DNA based therapeutic, such as RNAi molecules and antisense oligonucleotides, would function to decrease expression or function of a target gene or protein, or treat disease.
It is unknown in the art and not discussed in the disclosure regarding small molecule inhibitors that target any of the recited genetic subunits, or any inhibitors that have upstream or downstream effect on the function of the SAGA complex. Kassem et al (Not5-dependent co-translational assembly of Ada2 and Spt20 is essential for functional integrity of SAGA; NAR, 2016, 45(3): 1186-1199) teaches the SAGA complex participates in various transcriptional programs including binding to transcriptional activators, facilitating the assembly of the pre-initiation complex, interacting with the TATA binding protein TBP, and sharing a subunit with mRNA export complex TREX2 (pg. 1186, paragraph bridging col. 1 and 2). Kassem et al further demonstrates that Not2 of the Ccr4-Not complex associates with Ada2 subunit of the SAGA complex (pg. 1187, col. 1, para. 2), “GCN5, SPT20 and ADA2 mRNAs are tethered together and Not5 is important to retain Ada2 at this site of Spt20 production…allow[ing] correct SAGA assembly” (pg. 1187, col. 2, para. 2), and Not1 and Tdh3 are also needed for SAGA assembly (pg. 1195, col. 1-2). Therefore, prior art teaches the SAGA complex is connected to a vast number of transcriptional and translational complexes, and accordingly, the recited genus of inhibitors comprises a significant large number of undisclosed species including those that target complexes involved in SAGA assembly. Thus, the structure of the modified immune cells, is solely defined by the function of “a method of treating a subject in need there of”, without describing the population requiring treatment, without describing the structure of the immune cell and claim 6 does not further describe how the decreased expression of the SAGA complex occurs with the vastly claimed genus of agents.
While "examples explicitly covering the full scope of the claim language" typically will not be required, a sufficient number of representative species must be included to "demonstrate that the patentee possessed the full scope of the [claimed] invention." Lizardtech v. Earth Resource Mapping, Inc., 424 F.3d 1336, 1345, 76 USPQ2d 1724,1732 (Fed. Cir. 2005).
In the absence of sufficient recitation of distinguishing characteristics, the specification does not provide adequate written description of the claimed genus. One of skill in the art would not recognize from the disclosure that the applicant was in possession of the genus. Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features (see, Univ. of Rochester v. G.D. Searle& Co., 358 F.3d 916,927, 69 USPQ2d 1886,1895 (Fed. Cir. 2004); accord Ex Parte Kubin, 2007-0819, BPAI 31 May 2007, opinion at p. 16, paragraph 1). The specification does not clearly allow persons of ordinary skill in the art to recognize that he or she invented what is claimed (see Vas-Cath at page 1116).
Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. 112 is severable from its enablement provision (see page 1115).
Enablement
11. Claims 1-2, 4-6, 8, 10-11, 13, 20-22, 24, 27, 29, 42-45, and 49 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The factors considered when determining if the disclosure satisfies the enablement requirement and whether any necessary experimentation is undue include, but are not limited to: 1) nature of the invention, 2) state of the prior art, 3) relative skill of those in the art, 4) level of predictability, 5) existence of working samples, 6) breadth of claims, 7) amount of direction or guidance by the inventor, and 8) quantity of experimentation needed to make or use the invention. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
1) Nature of the invention and 6) Breadth of the claims
The nature of the invention is a method of treating a subject in need thereof, comprising administering to the subject a population of modified immune cells, which comprises one or more modified immune cells having decreased expression of one or more components of the SAGA (Spt-Ada- Gcn5-acetyltransferase) complex, relative to an unmodified immune cell (claim 1); wherein the modified immune cell comprises a nucleic acid encoding a chimeric antigen receptor (CAR) or a nucleic acid encoding a heterologous T cell receptor (TCR); wherein the CAR, the TCR, or both comprise an antigen-binding domain, wherein the antigen-binding domain specifically binds an antigen expressed on the surface of a tumor cell (claim 6); wherein the one or more components of the SAGA complex comprise USP22, TADA1, TADA2b, TAF6L, or any combination thereof (claim 10); wherein the expression of the one or more components of the SAGA complex is inhibited or blocked by contacting the immune cells with (i) a Cas9 protein and a CRISPR-cas system guide RNA (gRNA), (ii) an antisense oligonucleotide, (iii) an siRNA, (iv) an shRNA, (v) a small molecule inhibitor, (vi) a prime editing guide RNA, or (vii) any combination thereof (claim 11); wherein the subject is afflicted with a cancer; wherein the cancer comprises melanoma, bone cancer, renal cancer, prostate cancer, breast cancer, colon cancer, lung cancer, cutaneous or intraocular malignant melanoma, pancreatic cancer, skin cancer, cancer of the head or neck, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, non-Hodgkin's lymphoma (NHL), primary mediastinal large B cell lymphoma (PMBC), diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), transformed follicular lymphoma, splenic marginal zone lymphoma (SMZL), cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, chronic or acute leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia, acute lymphoblastic leukemia (ALL) (including non T cell ALL), chronic lymphocytic leukemia (CLL), solid tumors of childhood, lymphocytic lymphoma, cancer of the bladder, cancer of the kidney or ureter, carcinoma of the renal pelvis, neoplasm of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid cancer, squamous cell cancer, T-cell lymphoma, environmentally induced cancers including those induced by asbestos, other B cell malignancies or a combination thereof (claim 42 and 43).
Therefore, the nature of the invention is a chemical case, wherein there is natural unpredictability in performance of certain species or sub-combinations other than those specifically enumerated; See MPEP 2163. Accordingly, it is the Office’s position that undue experimentation would be required to make and use the claimed modified to treat the various cancers, with a reasonable expectation of success, because it would not be predictable from the disclosure of any particular species what other species may or may not work; See MPEP 2164.03.
The specification establishes the breadth of the claims by teaching that the modified immune cells of the invention are useful in the treatment of a variety of cancers, to inhibit the growth or proliferation of cancer cells and tumors comprising them (paragraph 72), including cancer can be selected from the group consisting of hematopoietic cell cancers and solid tumors. The specification teaches that conditions or disorders to be treated include benign or malignant tumors (e.g., renal, bladder, breast, gastric, ovarian, colorectal, prostate, pancreatic, lung, vulva, and thyroid); glioblastomas; and various head and neck tumors; leukemias and lymphoid malignancies.
The breadth of the claim exacerbates the complex nature of the subject matter to which the present claims are directed. Cancer is not a single disease, or cluster of closely related disorders. There are hundreds of cancers, which have in common only some loss of controlled cell growth. Cancers are highly heterogeneous at both the molecular and clinical level, something seen especially in, for example, the cancers of the breast, brain and salivary glands. They can occur in pretty much every part of the body. For example, there are solid cancers of the brain, spine, live, prostate, testes, ovaries, bile duct, blood vessels, lung and pleural cavity, thyroid, skin (including melanoma), colon, prostate, kidneys, breasts, testicles, vulva and vagina, uterus, cervix, fallopian tubes, thymus, stomach, esophagus, spleen, salivary glands, heart, oral cavity, adrenal glands, eye, head and neck, bladder, bone, and gall bladder. Each of these types of cancer have potentially dozens of sub-categories that each have unique physiological and etiological characteristics.
(5) The state of the prior art and (7) The predictability or unpredictability of the art
The state of the art regarding the use of modified immune cells which comprises decreased expression of one or more components of the SAGA complex to treat cancer is discussed by Prokakis, et al. (Prokakis, E., Dyas, A., Grün, R. et al. USP22 promotes HER2-driven mammary carcinoma aggressiveness by suppressing the unfolded protein response. Oncogene 40, 4004–4018 (2021). https://doi.org/10.1038/s41388-021-01814-5). Prokakis teaches that “USP22 was identified as a member of the so-called ‘death-from-cancer’ signature predicting therapy failure in cancer patients’ (abstract), and reports that “USP22 is required for the tumorigenic properties in murine and human HER2+-BC models” (abstract). In the Her2-positive breast cancer model, Prokakis found that genetic loss of USP22 increased disease-free survival, with “12.5% of USP22fl/fl mice never develop the disease” and concluded that its “findings demonstrate a critical tumor promoting role of USP22 in HER2-driven BC” (Results and Fig. 1). Prokakis also state tumor suppressive function for USP22 in colorectal cancer”. Prokakis concludes “these studies suggest an ambiguous and context dependent role of USP22 where it can have either tumor supportive or tumor suppressive functions” (Introduction and Discussion). Thus, the art teaches that decreasing the expression of the very SAGA subunit in the present applications supports tumorigenesis in one context while suppressing it in another.
Regarding the vast genus of tumors encompassed by the claims, While the state of the art is relatively high with regard to the treatment of specific cancer types, the state of the art with regards to treating all cancers with a single treatment is underdeveloped. In particular, there is no known anticancer agent that is effective against all cancer cell types. The cancer treatment art involves a very high level of unpredictability. Heppner et al. (Cancer Metastasis Review 2:5-23; 1983) discuss the heterogeneity of tumors from different tissues, as well as the same tissue. A key point made by Heppner et al. is that tumor heterogeneity contributes greatly to the sensitivity of tumors to drugs. Heppner et al. teach that as a tumor progresses to a metastatic phenotype, the susceptibility to a particular treatment can differ, and as such, makes predicting the responsiveness to treatment difficult. Additionally, Bally et al. (US Patent No. 5,595,756) stated, "Despite enormous investments of financial and human resources, no cure exists for a variety of diseases. For example, cancer remains one of the major causes of death. A number of bioactive agents have been found, to varying degrees, to be effective against tumor cells. However, the clinical use of such antitumor agents has been highly compromised because of treatment limiting toxicities (See column 1). Sporn et al. (Chemoprevention of Cancer, Carcinogenesis, Vol. 21 (2000), 525-530) teaches the magnitude of mortality of cancers and that mortalities are in fact still rising and that new approaches to a variety of different cancer are critically needed. Sporn et al. also teach that “given the genotype and phenotype heterogeneity of advanced malignant lesions as they occur in individual patients, one wonders just exactly what are the specific molecular and cellular targets for the putative cure.”
Furthermore, the art indicates the difficulties in going from in vitro to in vivo for drug development for treatment of cancers. Auerbach et al. (Cancer and Metastasis Reviews, 2000, 19: 167-172) indicate that one of the major problems in angiogenesis research has been the difficulty of finding suitable methods for assessing the angiogenic response. For example, the 96 well rapid screening assay for cytokinesis was developed in order to permit screening of hybridoma supernatants…In vitro tests in general have been limited by the availability of suitable sources for endothelial cells, while in vivo assays have proven difficult to quantitate, limited in feasibility, and the test sites are not typical of the in vivo reality (see p. 167, left column, 1st paragraph). Gura T (Science, 1997, 278(5340): 1041-1042) indicates that “the fundamental problem in drug discovery for cancer is that the model systems are not predictive at all” (see p. 1, 2nd paragraph). Furthermore, Gura T indicates that the results of xenograft screening turned out to be not much better than those obtained with the original models, mainly because the xenograft rumors don’t behave like naturally occurring tumors in humans—they don’t spread to other tissues, for example (see p. 2, 4th paragraph). Further, when patient’s tumor cells in Petri dishes or culture flasks and monitor the cells’ responses to various anticancer treatments, they don’t work because the cells simply fail to divide in culture, and the results cannot tell a researcher how anticancer drugs will act in the body (see p. 3, 7th paragraph). Furthermore, Jain RK (Scientific American, July 1994,58-65) indicates that the existing pharmacopoeia has not markedly reduced the number of deaths caused by the most common solid tumors in adults, among them cancers of the lung, breast, colon, rectum, prostate and brain (see p. 58, left most column, 1st paragraph). Further, Jain RK indicates that to eradicate tumors, the therapeutic agents must then disperse throughout the growths in concentrations high enough to eliminate every deadly cells…solid cancers frequently impose formidable barriers to such dispersion (see p. 58, bottom of the left most column continuing onto the top of the middle column). Jain RK indicates that there are 3 critical tasks that drugs must do to attack malignant cells in a tumor: 1) it has to make its way into a microscopic blood vessel lying near malignant cells in the tumor, 2) exit from the vessel into the surrounding matrix, and 3) migrate through the matrix to the cells. Unfortunately, tumors often develop in ways that hinder each of these steps (see p. 58, bottom of right most column). Thus, the art recognizes that going from in vitro studies to in vivo studies for cancer drug developments are difficult to achieve.
Hait (Nature Reviews/Drug Discovery, 2010, 9, pages 253-254) states that “The past three decades have seen spectacular advances in our understanding of the molecular and cellular biology of cancer. However, with a few notable exceptions, such as the treatment of chronic myeloid leukaemia with imatinib, these advances have so far not been translated into major increases in long-term survival for many cancers. Furthermore, data suggest that the overall success rate for oncology products in clinical development is -10%, and the cost of bringing a new drug to market is over US$1 billion.” (see page 253, left column, the 1st paragraph). Hait further teaches “The anticancer drug discovery process often begins with a promising target; however, there are several reasons why the eventual outcome for a particular cancer target may be disappointing. For example, the role of the target in the pathogenesis of specific human malignancies may be incompletely understood, leading to disappointing results”, “First, many targets lie within signal transduction pathways that are altered in cancer, but, owing to the complex nature of these pathways, upstream or downstream components may make modulating the target of little or no value”; “Second, target overexpression is often overrated. There are some instances in which overexpression predicts response to treatment.”; and “Another confounding factor is that cancer is more than a disease of cancer cells, as alterations in somatic or germline genomes, or both, create susceptibilities to transformational changes in cells and in the microenvironment that ultimately cooperate to form a malignant tissue. The putative role of cancer stem cells in limiting the efficacy of cancer therapeutics is also an area of intense interest. Therefore, effective treatments may require understanding and disrupting the dependencies among the multiple cellular components of malignant tissues. Single nucleotide polymorphisms in genes responsible for drug metabolism can further complicate the picture by affecting drug pharmacokinetics; for example, as with the topoisomerase inhibitor irinotecan.”, for example, page 253, Section “Understanding the target in context”. Hait also teaches “Drug effects in preclinical cancer models often do not predict clinical results, as traditional subcutaneous xenografting of human cancer cell lines onto immunocompromised mice produces ‘tumours’ that fail to recapitulate key aspects of human malignancies such as invasion and metastasis. Several improvements have been made, including orthotopic implantation and use of mice with humanized haematopoietic and immune systems. Newer genetic mouse models can also allow analyses of tumour progression from in situ through locally advanced and, in certain cases, widespread metastatic disease. However, whether or not these models will more accurately predict drug activity against human cancer remains to be determined. Other alternatives, including three-dimensional tissue culture or xenografts of fresh human biopsy specimens onto immunocompromised mice, have the potential advantage of including the human microenvironment. However, these approaches have yet to prove their value relative to their cost.”, for example, page 253, Section “Predictive models”. Furthermore, Hait teaches that “It is now widely thought that biomarkers will drive a personalized approach to cancer drug development. The aim is that they will cut costs, decrease time to approval, and limit the number of patients who are exposed to potential toxicities without a reasonable chance of benefit — as exemplified by the development of imatinib and trastuzumab. However, recent attempts at repeating these successes in other cancer types have been less successful.”, for example, page 254, Section “Stratified/personalized medicine”. The challenges facing cancer drug development are further confirmed and discussed in Gravanis et al (Chin Clin Oncol, 2014, 3, pages 1 -5). Gravanis et al teach “The generic mechanism of action for cytotoxics made the prediction of which tumor types might respond to them very difficult, if not impossible, and necessitated a ‘trial and error’ approach against many different types of tumors.” and “The most prominent change in oncology drug development in the last 20 years has been the shift from classic cytotoxics to drugs that affect signaling pathways implicated in cancer, which belong to the so called ‘targeted therapies’.”, for example, page 1, Section “From cytotoxics to targeted therapies: how far are we from truly personalized medicine?”. Gravanis et al. further teach “Although constantly progressing, an understanding of cancer biology is far from complete. The ability to develop new compounds or generate biological data predictive of the clinical situation relies on good quality basic research data, although the complexity and constantly evolving biology of the tumor may be to blame for the frequent non-reproducibility of research results. Systemic biology approaches of the -omic type still generate largely incomprehensible, mostly due to their volume, analytical data, few pieces of which are currently actionable/drug-g-able. Finally, animal models of cancer are similarly unable to predict the clinical situation (for example, page 3, right column, the 2nd paragraph).
Beans (PNAS 2018; 115(50): 12539-12543) teaches that across cancer types, 90% of cancer deaths are caused not by the primary tumor but by metastasis. Beans teaches that although some drugs may shrink metastases along with primary tumors, no existing drugs treat or prevent metastasis directly (See page 12540). Beans states “Without a targeted approach, metastatic tumors often reemerge. “We shrink them, we send them back to their residual state, and they reenact those survival functions and retention of regenerative powers that made them metastasis-initiating cells in the first place” (See page 12540). Beans teaches that one of the major scientific challenges of studying metastatic disease is that different forms of cancer seem to metastasize through different mechanisms and the same form of cancer may metastasize differently in different subsets of patients (See page 12542). Of note, Beans states “It’s unlikely that one researcher is going to find one pathway that proves to be the key to metastasis” (See page 12542). Bean also teaches that translating many findings into therapies also presents unique hurdles in that it is difficult to measure the effectiveness of the therapy. Secondary tumors are often minuscule, and therefore, measuring success by tumor shrinkage may not work. Measuring the incidence of metastasis after treatment is also more difficult (See page 12542).
Given Bally et al teaching of treatment-limiting toxicities in clinical use; Sporn's teaching that the cancer progression is heterogeneous as it progresses, both in genotype and phenotype; Auerbach et al teaching that one of the major problems in angiogenesis research has been the difficulty of finding suitable methods for assessing the angiogenic response; Gura's teaching that the models are unpredictable; Jain's teaching that the existing pharmacopoeia has not markedly reduced the number of deaths caused by the most common solid tumors in adults, among them cancers of the lung, breast, colon, rectum, prostate and brain; both Hait and Gravanis et al teaching various challenges facing cancer drug development, such as an understanding of cancer biology is far from complete, drug effects in preclinical cancer models often do not predict clinical results and many others; and Beans teachings that the field is highly underdeveloped with regards to preventing and treating cancer metastasis; the cited references demonstrate that the treatment of cancer is highly unpredictable, if even possible for many cancers.
6) The amount of direction or guidance provided by the inventor; 7) The existence of working examples:
The specification teaches in example 7 in the specification recites in vitro killing of A375 melanoma cancers cells transgenic NYESO-1+ T cells depleted of SAGA targets include gTADA1 KO, gTADA2b KO, and gTAF5L KO. Further tests in vivo demonstrated mice administered gTADA2b KO T NY-ESO 1 TCR+ T cells exhibited decreased melanoma tumor volume.
Thus, apart from a working example demonstrating that the modified immune cell exhibited decreased melanoma tumor volume in mice, the Applicant has not provided substantive evidence of treatment of any cancer. Because the diseases encompassed by the instant claims are so disparate and no single disease example can be representative of all the other encompassed diseases, a demonstration of treatment or support of a given condition does not provide support for the breadth of the claims.
Taken together, the art demonstrates that the treatment of cancer is highly unpredictable, if even impossible for many cancers. Moreover, the art provides evidence that the heterogeneity of tumors contributes to the variability in treating cancer. Accordingly, it follows that cancers that can be treated with the claimed modified immune cell can only be identified empirically. This constitutes undue experimentation. Therefore, given the lack of guidance in the art, the lack of working examples commensurate in scope to the claimed invention and the unpredictability of treating cancer, the specification, as filed does, not provide enablement for the claimed genus of cancers.
Applying the above test to the facts of record, it is determined that 1) no declaration under 37 C.F.R. 1.132 or other relevant evidence has been made of record establishing the amount of experimentation necessary, 2) insufficient direction or guidance is presented in the specification with respect to broadly treating cancer with the claimed modified immune cell, 3) the relative skill of those in the art is commonly recognized as quite high (post-doctoral level). One of skill in the art would require guidance, in order to make or use the claimed modified immune cell to treat the vast genus of cancers in a manner reasonable in correlation with the scope of the claims. Without proper guidance, the experimentation to is undue.
The Applicant has not provided sufficient guidance to enable one of skill in the art to make and use the claimed invention in a manner reasonably correlated with the scope of the claims broadly including all cancers. The scope of the claims must bear a reasonable correlation with the scope of enablement (In re Fisher, 166 USPQ 19 24 (CCPA 1970). Without such guidance, determining cancers that can be treated with the claimed modified immune cell, is unpredictable and the experimentation left those skilled in the art is unnecessarily and improperly, extensive and undue. See Amgen Inc v Chugai Pharmaceutical Co Ltd. 927 F 2d 1200, 18 USPQ2d 1016 (Fed. Cir. 1991) at 18 USPQ2d 1026-1027 and Exparte Forman, 230 U.S.P.Q. 546(Bd. Pat=. App & int. 1986).
In view of all of the above, one of skill in the art would be forced into undue experimentation to practice the claimed invention, and thus, the claimed invention does not satisfy the requirements of 35 U.S.C. 112 first paragraph.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
12. Claims 1, 10, 27 and 29 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Zhang, et al (Yana Zhang, Yajun Wang, Beixue Gao, Yueqi Sun, Liang Cao, Samantha M. Genardi, Chyung-Ru Wang, HuaBin Li, Zhaolin Sun, Yanjie Yang, Deyu Fang; USP22 controls iNKT immunity through MED1 suppression of histone H2A monoubiquitination. J Exp Med 4 May 2020; 217 (5): No Pagination Specified. doi: https://doi.org/10.1084/jem.20182218).
The instant claims are drawn to a method of treating a subject in need thereof, comprising administering to the subject a population of modified immune cells, which comprises one or more modified immune cells having decreased expression of one or more components of the SAGA (Spt-Ada- Gcn5-acetyltransferase) complex, relative to an unmodified immune cell.
Zhang, et al. teaches T cell-specific USP22 conditional KO mice in which Lck-Cre mediates USP22 deletion from the CD4/CD8 double negative stage such that mature T lineage cells are USP22 null (Results and Material and Methods, pages 2 and 12). Thus, deletion of USP22 constitutes decreased expression of a component of the SAGA complex. Zhang administered these cells to a subject by mixing them with WT marrow cells and a total of 10^7 mixed cells were transferred into lethally irradiated SJL mice by intravenous injection (Bone marrow chimera and adoptive transfer, page 12). Claim 1 recites no disease or condition to be treated. Thus, administration to the subject therefore meet “treating a subject in need thereof”. Therefore the administered population of modified immune cells (USP22-null t cells) which has the decreased expression of a component of SAGA complex, was administered to treating a subject in need thereof.
Regarding instant claim 10, the one or more components of the SAGA complex having decreased expression comprise USP22 (Abstract, introduction and material and methods, page 1-3 and 12).
Regarding claims 27 and 29, the properties of claims 27 and 29 are inherent properties that inherently flow from administering the modified immune cell having decreased expression of one or more components of the SAGA complex. The method of Zhang et al. administers the required modified immune cell comprising a deletion of USP22, and therefore the modified immune cells would inherently possess the properties recited in the instant claims. "Products of identical chemical composition cannot have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. Id.
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.
13. Claims 1, 2, 4, 5, 10, 11, 13, 42, 43 and 44 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim15, 16, 18 and 21 of copending Application No. 17,916,981.
Although the claims at issue are not identical, they are not patentably distinct from each other because copending claims 15, 16, 18, and 21 disclose a modified T cell wherein expression or function of one or more subunits of SAGA complex is inhibited and population of cells comprising the T cells. The specification of the copending claims teach that the population of cells is used in a method of treating cancer (pages 3, 4 and 6).
Although instant claims 1, 2, 4, 5, 10, 11, 13, 42, 43 and 44 are directed to a method of treating a subject with cancer, the specification of the ‘981 patent clearly teaches that the modified T cell wherein the expression or function of one or more subunits of SAGA complex is inhibited and population off cells comprising the T cells is used in a method of treating cancer (see pages 3, 4 and 6). In light of Pfizer, Inc. v. Teva Pharm. USA, Inc., 518 F.3d 1353, 86 USPQ2d 1001 (Fed. Cir. 2008) and especially in light of Geneva Pharmaceuticals Inc. v. GlaxoSmithKline PLC, 349 F3d 1373, 1385-86, 68 USPQ2d 1865, 1875 (Fed. Cir. 2003) and Sun Pharmaceutical Industries v. Eli Lilly and Co., 611 F. 3d 1381, 1385 (CAFC 2010) a method of treating a subject with cancer comprising administering to the subject a population of modified immune cells which comprises one or more modified immune cells having decreased expression of one or more components of the SAGA complex is an obvious variation of claims 15, 16, 18, and 21 of the ‘981 copending application because one would readily understand that the modified T cell with inhibition of a component of the SAGA complex of the ‘981 claims could be used for treating a disease caused by cancer.
Please note that when considering whether the invention defined in a claim of an application would have been an obvious variation of the invention defined in the claim of a patent, the disclosure of the patent may not be used as prior art. General Foods Corp. v. Studiengesellschaft Kohle mbH, 972 F.2d 1272, 1279, 23 USPQ2d 1839, 1846 (Fed. Cir. 1992). However, this does not mean that one is precluded from all use of the patent disclosure. For example, the patent may be consulted in order to determine the utility of a claimed compound. See Sun Pharmaceutical Industries v. Eli Lilly and Co., 611 F. 3d 1381, 1385 (CAFC 2010) (“Our prior obviousness-type double patenting decisions in Geneva and Pfizer, which addressed factual situations closely resembling that presently before the court, control this case. In both cases, we found claims of a later patent invalid for obviousness-type double patenting where an earlier patent claimed a compound, disclosing its utility in the specification, and a later patent claimed a method of using the compound for a use described in the specification of the earlier patent”).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
14. No claims are allowed.
15. Any inquiry concerning this communication or earlier communications from the examiner should be directed to Syed J Abbas whose telephone number is (571)272-0015. The examiner can normally be reached M-Th, 9:00AM-4:00PM.
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/SYED J ABBAS/Examiner, Art Unit 1674
/VANESSA L. FORD/Supervisory Patent Examiner, Art Unit 1674
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