Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
1. Claims 1-12 are pending in Applicant’s claim set filed 4/14/23. Claims 1 and 10 are independent claims.
2. The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
3. The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which Applicant may become aware in the specification.
4. 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.
5. Claims 1-12 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. This is a written description rejection.
Applicant has broadly claimed:
a) A pharmaceutical composition comprising engineered immune cells comprising disruption of SRC-3 (claim 1);
b) The pharmaceutical composition of claim 1 further comprising one or more agents that target SRC-3 (claims 4-8); and wherein the agent that targets SRC-3 is a small molecule inhibitor, an antibody, a protein, a nucleic acid, or a combination thereof (claim 9);
c) A pharmaceutical composition comprising an agent that targets the disruption of SRC-3 (claim 10), including wherein the agent is CRISPER, a TAL DNA binding domain, or zinc finger proteins (claim 11), or including wherein the agent targets a Treg (claim 12), and including the other limitations of the dependent claims.
As such, the one or more agents are functionally claimed where they are generically recited (i.e., “agent(s) that target SRC-3”, “an agent that targets the disruption of SRC-3”) or by broad class of molecule without recitation of specific nucleic acid or amino acid sequences (i.e., “small molecule inhibitor, an antibody, a protein, a nucleic acid, or a combination thereof”, “CRISPER”, “TAL DNA binding domain”, “zinc finger proteins”) and “wherein the agent targets a T regulatory cell” is a subgenus of an agent that has the functional property of disrupting SRC-3 as well as the functional property of targeting a Treg cell.
The specification does not disclose a representative number of species of such immune cells that are not CD4+CD25+ (+/-Foxp3+) Tregs, or do they provide a representative number of species of any immune cells that have different compositional structures because they have different disruptions of SRC-3, nor the claimed one or more agents that target SRC-3, nor sufficient relevant identifying characteristics in the form of structure or functional characteristics coupled with a known or disclosed correlation between structure and function.
An applicant shows possession of the claimed invention by describing the claimed invention with all of its limitations using such descriptive means as words, structures, figures, diagrams, and formulas that fully set forth the claimed invention. Lockwood v. Amer. Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997). Possession may be shown in a variety of ways including description of an actual reduction to practice, or by showing that the invention was "ready for patenting" such as by the disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the applicant was in possession of the claimed invention. See, e.g., Pfaff v. Wells Elecs., Inc., 525 U.S. 55, 68, 119 S.Ct. 304, 312, 48 USPQ2d 1641, 1647 (1998); Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406; Amgen, Inc. v. Chugai Pharm., 927 F.2d 1200, 1206, 18 USPQ2d 1016, 1021 (Fed. Cir. 1991) (one must define a compound by "whatever characteristics sufficiently distinguish it"). "Compliance with the written description requirement is essentially a fact-based inquiry that will ‘necessarily vary depending on the nature of the invention claimed.' " Enzo Biochem, 323 F.3d at 963, 63 USPQ2d at 1612. An invention described solely in terms of a method of making and/or its function may lack written descriptive support where there is no described or art-recognized correlation between the disclosed function and the structure(s) responsible for the function. See MPEP 2163 I.A.
An applicant may also show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. Enzo Biochem, 323 F.3d at 964, 63 USPQ2d at 1613 (quoting the Written Description Guidelines, 66 Fed. Reg. at 1106, n. 49, stating that "if the art has established a strong correlation between structure and function, one skilled in the art would be able to predict with a reasonable degree of confidence the structure of the claimed invention from a recitation of its function".). "Thus, the written description requirement may be satisfied through disclosure of function and minimal structure when there is a well-established correlation between structure and function." See MPEP 2163 II.3.
The specification discloses that in specific embodiments, the agent that targets SRC-3 is a small molecule inhibitor, an antibody, a protein, a nucleic acid, or a combination thereof. The specification discloses that the small molecule inhibitor may be Bufalin, gossypol, Verrucarin A, SI-2, SI-10, SI-12, a functional derivative thereof, or a combination thereof. The antibody may be a monoclonal or polyclonal antibody and specific examples include 5E11, LS-C801929, PA1-845, AX15.3, PA5-29854, EPR4374, or a combination thereof ([0010]). The specification further discloses that the nucleic acid may be CRISPER reagents ([0015]).
The specification discloses that the immune cells may be T cells, including Tregs ([0015]). The specification discloses that SRC-3 expression is highly enriched and correlated with Foxp3 in Tregs ([0019]). The specification exemplifies Foxp3 expressing Tregs from floxed SRC-3 mice backcrossed over 10 generations into the C57BL/6J background and crossed with a Foxp3-EGFP/CRE/ERT2 knock-in mouse also on a C57BL/6J background ([0021]). The specification also exemplifies CRISPER-based targeting of the SRC-3 gene in bulk T lymphocytes ([0022]). The specification discloses adoptive transfer of SRC-3 KO Tregs in a SRC-3 KO Treg mouse tumor model results in elimination of tumors ([0023], [0024]).
The specification discloses at [0030] that as used herein a “disruption” or “alteration” of a gene refers to the elimination or reduction of expression of one or more gene products encoded by the subject gene in a cell as compared to the level of expression of gene product in the absence of the alteration, with exemplary gene products including mRNA and protein products encoded by the gene. The alteration may be transient or reversible, and in other cases, permanent. In some embodiments, gene activity or function, as opposed to expression is disruption, with exemplary methods including gene silencing, knockdown, knockout, and/or gene alteration techniques such as gene editing. The specification discloses that the altered gene expression is carried out by effecting a disruption in the gene, such as a knock-out, insertion, missense or frameshift mutation such as biallelic frameshift mutation, deletion of all or part of the gene such as one or more exons or portions therefore, and/or knock-in. In some embodiments, the altered gene expression can be effected by sequence-specific or targeted nucleases, including DNA-binding targeted nucleases such as ZFNs, TALES or CRISPER-associated nuclease (Cas), specifically designed to be targeted to the sequence of the SRC-3 gene or a portion thereof ([0044], [0052]-[0066]). The specification discloses that the target sequence for SRC-3 may comprise any polynucleotide and the target sequence may be located in the nucleus or cytoplasm of the cell ([0067]).
There is no evidence of record for a representative number of species of such agents that target the disruption of SRC-3 either in the specification or the art. For instance, the low number of small molecule inhibitors (SMIs) disclosed in the specification have different structures, and the nucleic acids and nucleases are not disclosed by sequence, but only by function,
The specification discloses at [0032] that the term “subject” generally refers to an individual in need of treatment and can be any animal subject. The specification further discloses at [0087] that pharmaceutical compositions and formulations can be prepared by mixing the active ingredients with one or more optional pharmaceutically acceptable carriers in the form of lyophilized formulations or aqueous solutions, and that these carriers are generally nontoxic to recipients at the dosages and concentrations employed.
As is stated above, the one or more agents are functionally claimed where they are generically recited (i.e., “agent(s) that target SRC-3”, “an agent that targets the disruption of SRC-3”) or by a broad class of molecule without recitation of specific nucleic acid or amino acid sequences (i.e., “small molecule inhibitor, an antibody, a protein, a nucleic acid, or a combination thereof”, “CRISPER”, “TAL DNA binding domain”, “zinc finger proteins”). The identities of the small molecule inhibitors or the sequences of the nucleic acid or amino acid molecule inhibitors cannot be envisioned a priori. Experimentation must be engaged in to determine their identities. There is also no evidence for a representative number of species of such agents having the functional property that are structurally diverse and/or have diverse sequences for the broad and structurally diverse genus thereof. In addition, as there are many disruptors of SRC-3 that produce immune cells having different genetic disruptions, the identities of these cells cannot be envisioned a priori, and there is no evidence of record for a representative number of such immune cells.
In a non-limiting example for an agent that is an antibody, the art recognizes that the structures of the antibodies that bind to an antigen, an epitope of an antigen, or overlapping epitopes of an antigen have vastly diverse sequences and constitute a large genus.
As pertains to structure/function, the following evidentiary references teach the large structural diversity inherent in different antibodies that bind to a same or overlapping epitopes of an antigen.
Poosarla et al. (Biotechn. Bioeng., 2017, 114(6): 1331-1342) teach substantial diversity in designed mAbs (sharing less than 75% sequence similarity to all existing natural antibody sequences) that bind to the same 12-mer peptide, binding to different epitopes on the same peptide. Said reference further teaches “most B-cell epitopes…in nature consist of residues from different regions of the sequence and are discontinuous...de novo antibody designs against discontinuous epitopes present additional challenges...". (See entire reference.)
Khan and Salunke (J. Immunol, 2014, 192: 5398-5405) teach that two structurally diverse germline mAbs recognizing overlapping epitopes of the same short peptide do so in different topologies, the said antibodies possessing entirely different CDR sequences. Said reference teaches that unrelated mAbs structurally adjust to recognize an antigen, indicating that the primary B cell response is composed of BCRs having a high degree of structural adaptability. Said reference also teaches that the common epitope(s) also adopt distinct conformations when bound to different mAbs, with the higher degree of structural plasticity inherent to the mAbs. Said reference further teaches “It has been shown that both the framework region and the CDRs have a considerable amount of inherent conformational plasticity…Therefore, it is not surprising that distinct germline Abs recognize the same epitope by rearranging the CDR conformations. This may well have implications of Ag specificity beyond the naïve BCR repertoire, because Kaji et al….have shown in a recent report that the B cell memory can contain both germline-encoded and somatically mutated BCRs.” (See entire reference).
Lloyd et al. (Protein Engineering, Eng. Design & Selection, 2009, 22(3): 159-168) teach that a large majority of VH/VL germline gene segments are used in the antibody response to an antigen, even when the antibodies were selected by antigen binding. Said reference further teaches that in their studies, of the 841 unselected and 5,044 selected antibodies sequenced, all but one of the 49 functional VH gene segments was observed, and that there are on average about 120 different antibodies generated per antigen. Said reference also teaches that a wide variety of VH and VL pairings further increase diversity. (See entire reference.)
Edwards et al. (JMB, 2003, 334: 103-118) teach that over 1,000 different antibodies to a single protein can be generated, all with different sequences, and representative of almost the entire extensive heavy and light chain germline repertoire (42/49 functional heavy chain germlines and 33 of 70 V-lamda and V-kappa light chain germlines, and with extensive diversity in the HCDR3 region sequences (that are generated by VDJ germline segment recombination) as well.
Therefore, it appears that the instant specification does not adequately disclose the breadth of the immune cell and the agent having the functional property of targeting SRC-3 or that targets the disruption of SRC-3 recited in the instant composition claims. In light of this, a skilled artisan would reasonably conclude that Applicant was not in possession of the genus of all such immune cells and agents at the time the instant application was filed.
6. 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.
7. Claims 6, 8 and 12 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.
a) Claim 6 is indefinite in the recitation of “The composition of claim 4, wherein the cells and the one or more agents are not in the same formulation” because it is not clear what is meant, i.e., the specification does not disclose any limiting definition for “formulation”. It is therefore unclear how a composition comprising immune cells and one or more agents may be anything but in the same formulation as they are in the same composition.
b) Claim 8 is indefinite in the recitation of “The composition of claim 4, wherein the cells and the one or more agents are configured not to be delivered by the same route of administration” because it is not clear what is meant, i.e., they are in the same composition, so it follows that they are formulated to be administered together by the same route of administration.
c) Claim 12 is indefinite in the recitation of “wherein the agent targets a T regulatory cell” because it is not clear what is meant by “target” in the said context, i.e., it is not clear if it means that the agent that targets the disruption of SRC-3 targets a Treg because the Treg comprises amounts of SRC-3 or that the agent that targets disruption of SRC-3 also targets something else that is specific to a Treg.
8. In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
9. Claim interpretation: The specification discloses at [0032] that the term “subject” generally refers to an individual in need of treatment and can be any animal subject. The specification further discloses at [0087] that pharmaceutical compositions and formulations can be prepared by mixing the active ingredients with one or more optional pharmaceutically acceptable carriers in the form of lyophilized formulations or aqueous solutions, and that these carriers are generally nontoxic to recipients at the dosages and concentrations employed. The specification discloses at [0030] that as used herein a “disruption” or “alteration” of a gene refers to the elimination or reduction of expression of one or more gene products encoded by the subject gene in a cell as compared to the level of expression of gene product in the absence of the alternation, with exemplary gene products including mRNA and protein products encoded by the gene. The alteration may be transient or reversible, and in other cases, permanent. In some embodiments, gene activity or function, as opposed to expression is disruption, with exemplary methods including gene silencing, knockdown, knockout, and/or gene alteration techniques such as gene editing. Given the indefiniteness of dependent claim 12 as enunciated above, the agent that targets a Treg cell is being interpreted as an agent that agent that targets the disruption of SRC-3 because the Treg comprises amounts of SRC-3 or that the agent that targets disruption of SRC-3 also targets something else that is specific to a Treg. With regard to “pharmaceutical composition” recited in the instant claims, the term “pharmaceutical” must be weighed with the structural limitations of the claim. If the composition merely comprises a known composition, the term carries little weight absent evidence of structural difference.
10. 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.
11. Independent claim 10 recites: A pharmaceutical composition, comprising an agent that targets the disruption of SRC-3.
12. Claims 10 and 12 are rejected under 35 U.S.C. 102(a)(i) as being anticipated by Xu et al. (PNAS, 2000, 97(12): 6379-6384, IDS reference).
Xu et al. teach a targeting vector that disrupts the SRC-3 gene (see entire reference, especially Results paragraph 1, Fig. 1 and legend, and first paragraph on page 6380). Although the art reference does not explicitly teach that the vector is comprised with a nontoxic carrier, the cells were transfected without toxicity, and the vector necessarily must inherently be comprised in a carrier in order to be transfected into the ES cells. With regard to “pharmaceutical composition” recited in the instant claims, the term “pharmaceutical” must be weighed with the structural limitations of the claim. If the composition merely comprises a known composition, the term carries little weight absent evidence of structural difference. As noted above in the claim interpretation section above in this office action, due to the indefiniteness of claim 12, the limitation “wherein the agent targets a T regulatory cell” is being interpreted as the agent that targets the disruption of SRC-3 is also targeting a Treg because the Treg comprises SRC-3.
13. Claims 10 and 12 are rejected under 35 U.S.C. 102(a)(i) as being anticipated by Song et al. (PNAS, 2016, 113(18): 4970-4975, IDS reference).
Song et al. teach a small molecule inhibitor SI-2 in phosphate buffer (a pharmaceutically acceptable buffer) that was administered to mice (see entire reference, especially paragraph spanning pages 4973-4974, Figure 4 and legend, and paragraph spanning columns 1-2 on page 4974). As noted above in the claim interpretation section of this office action, due to the indefiniteness of claim 12, the limitation “wherein the agent targets a T regulatory cell” is being interpreted as the agent that targets the disruption of SRC-3 is also targeting a Treg because the Treg comprises SRC-3.
14. Claims 10 and 12 are rejected under 35 U.S.C. 102(a)(i) as being anticipated by Wang et al. (Mol. Endocrinol. 2011, 25(12): 2041-2053, IDS reference).
Wang et al. teach that gossypol, an SRC-3 small molecule inhibitor, was administered in clinical trials of patients with several types of cancers (i.e., in a pharmaceutical composition, see entire reference, especially page 2049 at the last paragraph, sentence prior to results section, results section). As noted above in the claim interpretation section of this office action, due to the indefiniteness of claim 12, the limitation “wherein the agent targets a T regulatory cell” is being interpreted as the agent that targets the disruption of SRC-3 is also targeting a Treg because the Treg comprises SRC-3.
15. Claims 1-3 are rejected under 35 U.S.C. 102(a)(i) as being anticipated by Tanaka et al. (Cell Reports 5/22/2018, 23: 2318-2329, IDS reference) as evidenced by Singer, Bernhard. (2013, Re: How does culture with anti-CD3/anti-CD28 mAb alone compare to culture with anti-CD3/anti-CD28 mAb and subsequent treatment with PMA/Ionomycine?. Retrieved from: https://www.researchgate.net/post/How-does-culture-with-anti-CD3-anti-CD28-mAb-alone-compare-to-culture-with-anti-CD3-anti-CD28-mAb-and-subsequent-treatment-with-PMA-Ionomycine/51812f7ccf57d7a07600002a/citation/download, one page) and Tran et al. (Blood, 2007, 110: 2983-2990).
Independent claim 1 recites: A pharmaceutical composition, comprising engineered immune cells comprising disruption of steroid receptor coactivator-3 (SRC-3).
Tanaka et al. teach an engineered CD4+ T cell comprising a disruption of SRC-3 (from an SRC-3 conditional mouse knockout), wherein the T cell is a Treg. Tanaka et al. inherently teach that the cells were placed in a buffer, as they teach that the cells were analyzed by FACs or they were washed prior to being restimulated with anti-CD3 (see entire reference, especially page 2320 at paragraph 2 and column 2, paragraph 2, page 2322, column 2 at paragraph 3). With regard to “pharmaceutical composition” recited in the instant claims, the term “pharmaceutical” must be weighed with the structural limitations of the claim. If the composition merely comprises a known composition, the term carries little weight absent evidence of structural difference.
Although the art reference does not teach wherein the SRC-3 disrupted naïve CD4+ T cell is CD25+ and or CD25+ and FoxP3+, it does teach that it is an induced Treg (iTreg) that was differentiated from CD4+CD25- SRC-3 knockout T cells by treating with anti-CD3/anti-CD28 followed by treatment with PMA/ionomycin or with mIL-2, mTGF-b, anti-IFNg, and anti-IL-4 followed by stimulation with PMA/ionomycin (e.g., experimental procedures section). Evidentiary reference Singer teaches that treatment of mononuclear cells with PMA/ionomycin causes expression of CD25. Evidentiary reference Tran et al. teaches that mouse naïve Tregs (nTregs) or those generated in vitro after TCR stimulation (such as with anti-CD3 as taught by Tanaka et al.) in the presence of TGF-b (also as taught by Tanaka et al.) induces expression of Foxp3 (first sentence of the Discussion section). Although the art reference does not explicitly disclose that the buffier or wash solution the cells were comprised in is a pharmaceutically acceptable carrier, the definition of such is nontoxic at certain concentrations. In addition, the active ingredient are the induced Treg cells. As stated above, there is a lack of evidence that the recitation of “pharmaceutical composition” imparts a structural difference upon the iTregs. Therefore, the claimed product appears to be the same as the product of the prior art absent a showing of differences. Since the Patent Office does not have the facilities for examining and comparing the product of the instant invention to those of the prior art, the burden is on Applicant to show a distinction between the product of the instant invention and that of the prior art. See In re Best, 562 F.2d 1252, 195 USPQ 430 (CCPA 1977).
16. Claims 10-12 are rejected under 35 U.S.C. 102(a)(i) as being anticipated by
WO2015164818 A1.
WO2015164818 A1 teaches an agent that targets SRC-3 that is an shRNA, MiRNA, zinc finger proteins, or small molecule inhibitor that is administered to reduce the expression of SRC-3 on a cancer cell. The said reference inherently teaches a pharmaceutical composition comprising the agent. The said reference also teaches a therapeutic delivery system comprising a therapeutic agent carrier (see entire reference, especially page 15 at lines 10-21, claims, abstract). As noted above in the claim interpretation section of this office action, due to the indefiniteness of claim 12, the limitation “wherein the agent targets a T regulatory cell” is being interpreted as the agent that targets the disruption of SRC-3 is also targeting a Treg because the Treg comprises SRC-3.
17. Claims 10-12 are rejected under 35 U.S.C. 102(a)(i) as being anticipated by
US 9,683,237.
US 9,683,237 discloses an agent that targets SRC-3 that is an shRNA, MiRNA, zinc finger proteins, or small molecule inhibitor that is administered to reduce the expression of SRC-3 on a cancer cell. The said reference inherently teaches a pharmaceutical composition comprising the agent. The said reference also teaches a therapeutic delivery system comprising a therapeutic agent carrier (see entire reference, especially abstract, (11), (22)). As noted above in the claim interpretation section of this office action, due to the indefiniteness of claim 12, the limitation “wherein the agent targets a T regulatory cell” is being interpreted as the agent that targets the disruption of SRC-3 is also targeting a Treg because the Treg comprises SRC-3.
18. Claims 10 and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Eedunuri et al. (Mol. Endocrinol. 2015, 29(8): 1170-1183, IDS reference).
Eedunuri et al. teach a miRNA that targets the disruption of SRC-3 and that it is to be used as a monotherapy (i.e., a pharmaceutical composition) to treat certain tumors (see entire reference, especially page 1180 at column 1 at the first full paragraph, last paragraph of reference, and abstract).
Eedunuri et al. inherently teach a pharmaceutical composition comprising the said miRNA. As noted above in the claim interpretation section of this office action, due to the indefiniteness of claim 12, the limitation “wherein the agent targets a T regulatory cell” is being interpreted as the agent that targets the disruption of SRC-3 is also targeting a Treg because the Treg comprises SRC-3.
19. The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
20. Claims 1-3 are rejected under 35 U.S.C. 103 as being unpatentable over Tanaka et al. (Cell Reports 5/22/2018, 23: 2318-2329, IDS reference) in view of Tran et al. (Blood, 2007, 110: 2983-2990), and as evidenced by Singer, Bernhard. (2013), Re: How does culture with anti-CD3/anti-CD28 mAb alone compare to culture with anti-CD3/anti-CD28 mAb and subsequent treatment with PMA/Ionomycine?. Retrieved from: https://www.researchgate.net/post/How-does-culture-with-anti-CD3-anti-CD28-mAb-alone-compare-to-culture-with-anti-CD3-anti-CD28-mAb-and-subsequent-treatment-with-PMA-Ionomycine/51812f7ccf57d7a07600002a/citation/download,
Tanaka et al. teach an engineered CD4+ T cell comprising a disruption of SRC-3 (from an SRC-3 conditional mouse knockout), wherein the T cell is a Treg. Tanaka et al. inherently teach that the cells were placed in a buffer, as they teach that the cells were analyzed by FACs or they were washed prior to being restimulated with anti-CD3 (see entire reference, especially page 2320 at paragraph 2 and column 2, paragraph 2, page 2322, column 2 at paragraph 3).
Tanaka et al. do not explicitly teach wherein the iTregs are present in a pharmaceutical composition.
Tran et al. teach that mouse naïve Tregs (nTregs) or those generated in vitro after TCR stimulation (such as with anti-CD3 as taught by Tanaka et al.) in the presence of TGF-b (also as taught by Tanaka et al.) induces expression of Foxp3 and these cells exert potent suppressor function in vitro and can prevent or control disease in vivo (i.e., the art reference inherently teaches a pharmaceutical composition comprising a pharmaceutically acceptable carrier, see entire reference, especially first sentence of the Discussion section, page 2983 at column 2 at the first full paragraph).
It would have been prima facie obvious to one of ordinary skill in the art before the filing date of the claimed invention to have placed the iTregs taught by the primary art reference in a pharmaceutical composition as taught by the secondary art reference.
One of ordinary skill in the art would have been motivated to do this, and with a reasonable expectation of success in doing so, in order to make a composition suitable for studying Treg function in vivo.
Although the primary art reference does not explicitly teach wherein the SRC-3 disrupted naïve CD4+ T cell is CD25+ and or CD25+ and FoxP3+, it does teach that it is an induced Treg (iTreg) that was differentiated from CD4+CD25- SRC-3 knockout T cells by treating with anti-CD3/anti-CD28 followed by treatment with PMA/ionomycin or with mIL-2, mTGF-b, anti-IFNg, and anti-IL-4 followed by stimulation with PMA/ionomycin (e.g., experimental procedures section). Evidentiary reference Singer teaches that treatment of mononuclear cells with PMA/ionomycin causes expression of CD25. Therefore, the claimed product appears to be similar to the product of the prior art absent a showing of unobvious differences. Since the Patent Office does not have the facilities for examining and comparing the product of the instant invention to those of the prior art, the burden is on Applicant to show a distinction between the product of the instant invention and that of the prior art. See In re Best, 562 F.2d 1252, 195 USPQ 430 (CCPA 1977).
21. 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.
22. Claims 1-10 and 12 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4 of U.S. Patent No. 11,633,428.
The claims of U.S. Patent No. 11,633,428 are drawn to a composition comprising an engineered immune cell comprising disruption of SRC-3 and one or more agents that target SRC-3, wherein the immune cell is a Treg cell that is CD4+ and CD25+ or one that is CD4+ CD25+ FoxP3+, and including wherein the two components are in the same formulation, and including wherein the agent that targets SRC-3 is a small molecule inhibitor, an antibody, a protein, a nucleic acid or a combination thereof. With regard to “pharmaceutical composition” recited in the instant claims, the term “pharmaceutical” must be weighed with the structural limitations of the claim. If the composition merely comprises a known composition, the term carries little weight absent evidence of structural difference. The existence of an unobvious structural difference would define over the prior art; however, in the instant case, the claims of ‘428 recite the same cell as that recited in the instant claims. Therefore, the claimed product appears to be the same as the product of the claims of ‘428 absent a showing of unobvious differences. Since the Patent Office does not have the facilities for examining and comparing the product of the instant invention to those of the claims of ‘428, the burden is on Applicant to show an unobvious distinction between the product of the instant invention and that of the prior art. See In re Best, 562 F.2d 1252, 195 USPQ 430 (CCPA 1977). Alternatively, it would have been prima facie obvious to one of ordinary skill in the art to have comprised the composition with a pharmaceutically acceptable carrier as the art recognized before the filing date of the claimed invention that adoptive transfer of a pharmaceutical composition comprising CD4+ CD25+ FoxP3+ Tregs into patients with GVHD could be beneficial, for example, as evidenced by Theil et al. (Cytotherapy, 2015, 17: 473-486, see entire reference, especially abstract). As noted above in the claim interpretation section of this office action, due to the indefiniteness of claim 12, the limitation “wherein the agent targets a T regulatory cell” is being interpreted as the agent that targets the disruption of SRC-3 is also targeting a Treg because the Treg comprises SRC-3.
23. Claims 1-5, 7, 9, 10 and 12 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 of U.S. Patent No.11,633,429 or including in view of Theil et al. (Cytotherapy, 2015, 17: 473-486).
Note that the US application serial no. 17/650,645 issued as US 11,633,429. The present application is a CON of serial no. 17/650,645. The claims in serial no. 17/650,645 were exclusively drawn to a method. The instant application is not a divisional application of parent application serial no. 17/650,645, but is rather a continuing application.
The claims of US 11,633,429 are drawn to a method of producing engineered CD4+ Tregs comprising a disruption of endogenous SRC-3 by a step of exposing the Tregs to one or more agents that disrupt expression of endogenous SRC-3 in the Tregs, including wherein the agents comprise nucleic acid or CRISPR reagents, small molecule inhibitors, antibodies, proteins or a combination thereof, and including wherein the Tregs are also CD25+ and/or FoxP3+. The engineered SRC-3 disrupted CD4+/CD25+/FoxP3+ Tregs as well as the one or more agents that disrupt expression of endogenous SRC-2 in the Tregs recited in the method claims of ‘429 are anticipated by the said method that makes and uses them, respectively.
The claims of ‘429 however, do not recite that the Tregs or the agents are comprised in a pharmaceutical composition.
It would have been prima facie obvious to one of ordinary skill in the art to have comprised the SRC-3 disrupted Tregs in a buffer such as PBS (i.e., a pharmaceutical buffier). One of ordinary skill in the art would have been motivated to do this in order to store them after the selection step. It would have been prima facie obvious to one of ordinary skill in the art to have comprised the agent(s) in PBS (i.e., a pharmaceutical buffier). One of ordinary skill in the art would have been motivated to do this in order to comprise the agent in a buffer that is physiologically compatible with the Tregs for use in the method recited in the claims of ‘429. With regard to “pharmaceutical composition” recited in the instant claims, the term “pharmaceutical” must be weighed with the structural limitations of the claim. If the composition merely comprises a known composition, the term carries little weight absent evidence of structural difference. The existence of an unobvious structural difference would define over the prior art, however, in the instant case, the claims of ‘429 recite the same cell as that recited in the instant claims.
Alternatively, Theil et al. teach that adoptive transfer of a pharmaceutical composition comprising CD4+ CD25+ FoxP3+ Tregs into patients with GVHD could be beneficial (see entire reference, especially abstract).
It would therefore have been prima facie obvious to one of ordinary skill in the art before the filing date of the claimed invention to have placed the SRC-3-disrupted Tregs recited in the method claims of US 11,633,429 in a pharmaceutical composition as taught by Theil et al.
One of ordinary skill in the art would have been motivated to do this in order to comprise the Tregs in a composition that could be used to treat patients having GVHD.
As noted above in the claim interpretation section of this office action, due to the indefiniteness of claim 12, the limitation “wherein the agent targets a T regulatory cell” is being interpreted as the agent that targets the disruption of SRC-3 is also targeting a Treg because the Treg comprises SRC-3.
24. Claims 10-12 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of U.S. Patent No. 11,497,772.
Note that US 11,497,772 issued from application serial no. 17/446,282 that is the grandparent application of the instant application. The restriction requirement in 17/446,282 was made between the engineered SRC-3-disrupted immune cell that is a Treg, treating cancer comprising administering the said cell, and a method of producing the said immune cells. There were no claims that were present in 17/466,282 that were drawn to a pharmaceutical composition comprising an agent that targets the disruption of SRC-3, to which instant claims 10 and 12 are drawn. Therefore, the following double patenting rejection is set forth below.
The claims of US 11,497,772 are drawn to a method for treating cancer comprising administering engineered immune cells that are Tregs (including those that are CD4+CD25+Foxp3+) comprising disruption of SRC-3, and wherein the method further comprises a step of exposing the cells ex vivo to an effective amount of one or more agents that target SRC-3 sufficient to modify the cells, and wherein the agents may include a small molecule inhibitor, an antibody, a protein, a nucleic acid, or a combination thereof, or wherein the method comprises administering a therapeutically effective amount of a composition comprising both engineered Tregs comprising disruption of SRC-3 and one or more agents that target SRC-3. The cells and the agents may be in the same or different formulations via a variety of different or same formulations. The recitation of the said agent and the said cells in the method anticipates the said agent and the said cells. With regard to “pharmaceutical composition” recited in the instant claims, the term “pharmaceutical” must be weighed with the structural limitations of the claim. If the composition merely comprises a known composition, the term carries little weight absent evidence of structural difference.
25. Claims 10-12 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of U.S. Patent No. 9,683,237 (IDS reference) in view of WO2015164818 A1.
The claims of US 9,683,237 are drawn to a bifunctional shRNA composition capable of reducing expression of three or more genes and comprising a first, second and third bifunctional RNA molecule that reduce the expression of target genes, wherein at least one nucleic acid sequence is defined by SEQ ID NOs: 2, 4, 40 or 41 (which disrupt KRAS tumor protein gene as is evidenced by e.g., column 5 at lines 19-25 of the specification of US 9,683,237).
The claims of US 9,683,237 do not recite wherein at least one of the other two RNAs targets the disruption of SRC-3.
WO2015164818 A1 teaches an agent/expression vector thereof/delivery system thereof comprising a therapeutic agent carrier (i.e., a pharmaceutical composition) that targets SRC-3 that is an shRNA, MiRNA, zinc finger proteins, or small molecule inhibitor that is administered to reduce the expression of SRC-3 on a cancer cell. The said reference inherently teaches a pharmaceutical composition comprising the agent. The said reference also teaches a therapeutic delivery system comprising a therapeutic agent carrier (see entire reference, especially page 15 at lines 10-21, claims, abstract). In addition, WO2015164818 A1 further teaches a composition comprising RNA capable of reducing expression of two or more or at least three genes, wherein the genes include mutated KRAS, and SRC-3 amongst others (e.g., abstract). As noted above in the claim interpretation section of this office action, due to the indefiniteness of claim 12, the limitation “wherein the agent targets a T regulatory cell” is being interpreted as the agent that targets the disruption of SRC-3 is also targeting a Treg because the Treg comprises SRC-3.
It would have been prima facie obvious to one of ordinary skill in the art before the filing date of the claimed invention to have used an RNA molecule that inhibits the expression of SRC-3 as one of the molecules in the composition recited in the claims of US 9,683,237.
One of ordinary skill in the art would have been motivated to do this, and with a reasonable expectation of success in doing so, in order to target expression of two genes involved with cancers.
Claims 10-12 are directed to an invention not patentably distinct from claims 1-10 of commonly assigned US 9,683,237, as enunciated supra. The U.S. Patent and Trademark Office may not institute a derivation proceeding in the absence of a timely filed petition. The USPTO normally will not institute a derivation proceeding between applications or a patent and an application having common ownership (see 37 CFR 42.411). Commonly assigned US 9,683,237, discussed above, may form the basis for a rejection of the noted claims under 35 U.S.C. 102 or 103 if the commonly assigned case qualifies as prior art under 35 U.S.C. 102(a)(2) and the patentably indistinct inventions were not commonly owned or deemed to be commonly owned not later than the effective filing date under 35 U.S.C. 100(i) of the claimed invention.
In order for the examiner to resolve this issue the applicant or patent owner can provide a statement under 35 U.S.C. 102(b)(2)(C) and 37 CFR 1.104(c)(4)(i) to the effect that the subject matter and the claimed invention, not later than the effective filing date of the claimed invention, were owned by the same person or subject to an obligation of assignment to the same person. Alternatively, the applicant or patent owner can provide a statement under 35 U.S.C. 102(c) and 37 CFR 1.104(c)(4)(ii) to the effect that the subject matter was developed and the claimed invention was made by or on behalf of one or more parties to a joint research agreement that was in effect on or before the effective filing date of the claimed invention, and the claimed invention was made as a result of activities undertaken within the scope of the joint research agreement; the application must also be amended to disclose the names of the parties to the joint research agreement.
A showing that the inventions were commonly owned or deemed to be commonly owned not later than the effective filing date under 35 U.S.C. 100(i) of the claimed invention will preclude a rejection under 35 U.S.C. 102 or 103 based upon the commonly assigned case. Alternatively, applicant may take action to amend or cancel claims such that the applications, or the patent and the application, no longer contain claims directed to patentably indistinct inventions.
26. Claims 1-3 and 10 are objected to because of the following informalities:
Claims 1 and 10 are objected to because a comma is not required after “composition” and before “comprising” at line 1 of each said claim.
Claims 2 and 3 are objected to because the plus signs “+” should be superscripted ‘+’.
Appropriate correction is required.
27. No claim is allowed.
28. Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARIANNE DIBRINO whose telephone number is (571)272-0842. The examiner can normally be reached on M, T, Th, F.
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/Marianne DiBrino/
Marianne DiBrino, Ph.D.
Patent Examiner
Group 1640
Technology Center 1600
/MICHAEL SZPERKA/Primary Examiner, Art Unit 1641