DETAILED ACTION
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 .
Claims status
Applicants supplemental claim amendments and reply filed 1/30/2024 is acknowledged.
Claims 12-20 is/are cancelled and claims 21 is/are newly added. Claims 1-11, 21 is/are currently pending and is/are under examination.
Withdrawn Objections
The objections presented herein represent the full set of objections currently pending in this application. Any objections not specifically reiterated are hereby withdrawn.
Claim Rejections - 35 USC § 112(d) – New, in light of amendments
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 8 and 9 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 8 recites a leukemia cell as the recombinant human target cell which broadens the scope of claim 1 since claim 1 limits the recombinant human target cell to a specific leukemia cell type i.e. SUP-B15.
Claim 9 recites SUP-B15 as the recombinant human target cell which does not further limit the recombinant human target cell of claim 1 since claim 1 already limits the recombinant human target cell to a specific leukemia cell type to a SUP-B15 cell.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 112(b) – New, in light of amendments
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 21 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 21 recites the broad recitation “wherein the transmembrane antigen is a tumor associated antigen, a tumor specific antigen, or a patient- and tumor specific antigen”, and the claim also recites “wherein the transmembrane antigen is PD-L1, CD33, CD123, HER-2, or CD20” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claim Rejections - 35 USC § 103
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Rejection of Claims 1, 3, 5-7 and 13 under 35 U.S.C. 103 as being unpatentable over Uherek et al (Retargeting of natural killer–cell cytolytic activity to ErbB2-expressing cancer cells results in efficient and selective tumor cell destruction. Blood, Volume 100, August 2002) as evidenced by Maurer-Gebhard et al (Systemic Treatment with a Recombinant erbB-2 Receptor-specific Tumor Toxin Efficiently Reduces Pulmonary Metastases in Mice Injected with Genetically Modified Carcinoma Cells. Cancer Research, Volume 58, June 1998) is withdrawn because Uherek does not teach a SUP-B15 recombinant cell.
Rejection of Claims 1, 4-7 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Muller et al (Expression of a CD20-specific chimeric antigen receptor enhances cytotoxic activity of NK cells and overcomes NK-resistance of lymphoma and leukemia cells. Cancer Immunol Immunother, Volume 57, August 2007) is withdrawn because Muller does not teach a SUP-B15 recombinant cell.
Claims 1, 3, 5, 8-11 and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Chen et al (Stromal cells attenuate the cytotoxicity of imatinib on Philadelphia chromosome-positive leukemia cells by up-regulating the VE-cadherin/β-catenin signal. Leukemia Research, Volume 38, October 2014; reference of record) and Uherek et al (Retargeting of natural killer–cell cytolytic activity to ErbB2-expressing cancer cells results in efficient and selective tumor cell destruction. Blood, Volume 100, August 2002; reference of record) in view of Hasenkamp et al (Resistance Against Natural Killer Cell Cytotoxicity: Analysis of Mechanisms. Scandinavian Journal of Immunology, Volume 64, 2006; reference of record).
Chen teaches a SUP-B15 cell expressing VE-cadherin transmembrane antigen under the CMV promoter (Materials and Methods: Stable overexpression of VE-cadherin in Ph+ leukemia cells) i.e. a recombinant human target cell (required for claims 1, 8, 9).
Chen does not teach a transmembrane antigen that is a tumor associated antigen, a tumor specific antigen, or a patient- and tumor specific antigen that is present on a solid tumor and is one of PD- L1, CD33, CD123, HER-2, or CD20.
Uherek teaches HER-2 as a breast tumor associated antigen which is a solid tumor (page 1271, right column, last line) (required for claims 1, 3, 5). Uherek also teaches several recombinant cells (mouse and human) with and without HER2 transmembrane antigens that show less than 10% lysis in the presence of NK cells that do not comprise a HER2-targeting CAR (i.e. background/spontaneous lysis) at 1:1 effector to target cell ratio. In the presence of NK cells that comprise HER2-targeting CAR, Uherek shows that only recombinant cells that comprise the HER2 transmembrane antigen are lysed at level greater than 10% (i.e. specific/targeted lysis). See Figures 2, 3, 4.
Chen and Uherek do not teach that the spontaneous i.e. background lysis of recombinant SUP-B15 expressing a tumor-associated antigen such as HER-2 is less than 20% in the presence of NK cells at an effector cell to recombinant cell ratio of 1 or less, however Hasenkamp teaches that SUP-B15 cells show less than 10% lysis in presence of NK cells at an effector cell to target cell ratio of 1 or less (Figure 1B) (required for claim 1, 10-11 and 21). Further, Hasenkamp teaches that SUP-B15 is resistant to NK cell targeting by stating that “We conclude that SupB15 escapes from recognition as NK cell target because of appropriate inhibitory KIR ligand expression and by lacking ligands to stimulate NK cell receptors” (page 448). Therefore, Hasenkamp teaches that SUP-B15 shows low (less than 10%) background/ spontaneous lysis in the presence of NK cells since SUP-B15 lack the transmembrane antigen required by NK-cells for targeting.
Therefore, it would be obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to substitute the VE-Cadherin transmembrane antigen of Chen with the HER-2, a tumor associated antigens of Uherek to yield a predictable result of a recombinant SUP-B15 expressing a HER-2, tumor associated antigen. An ordinary artisan would be motivated to perform this substitution so they can use a leukemia-specific cell line, such as SUP-B15 taught by Chen, in cytotoxicity assays, such as that of Uherek, to test the specificity of newly developed CAR-NK or CAR-T cells. An ordinary artisan would reasonably expect that the recombinant SUP-B15 expressing a HER-2 produced by combination of Chen and Uherek would exhibit less than 10% spontaneous lysis because Hasenkamp teaches that SUP-B15 cells are resistant to NK cell targeting and Uherek teaches that NK cells do not target HER2 expressing cells unless NK cells are modified to express HER2-targeting CAR.
Claims 1, 4, 5, 8-11 and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Chen et al (Stromal cells attenuate the cytotoxicity of imatinib on Philadelphia chromosome-positive leukemia cells by up-regulating the VE-cadherin/β-catenin signal. Leukemia Research, Volume 38, October 2014; reference of record) and Hoseini et al (Acute myeloid leukemia targets for bispecific antibodies. Blood Cancer Journal, Volume 7, February 2017; reference of record) in view of Hasenkamp et al (Resistance Against Natural Killer Cell Cytotoxicity: Analysis of Mechanisms. Scandinavian Journal of Immunology, Volume 64, 2006; reference of record).
Chen teaches a recombinant human target cell that is a leukemia SUP-B15 cell expressing VE-cadherin transmembrane antigen under the CMV promoter (Materials and Methods: Stable overexpression of VE-cadherin in Ph+ leukemia cells) (required for claims 1, 8 and 9).
Chen does not teach a transmembrane antigen that is a tumor associated antigen, a tumor specific antigen, or a patient- and tumor specific antigen that is present on a liquid tumor and is one of PD- L1, CD33, CD123, or CD20.
Hoseini teaches liquid tumor antigens such as PD-L1, CD33, CD123 and CD20 as leukemia associated antigens (Table 1). Hoseini also discloses use of human leukemia cell lines that express PD-L1 and PD-L2 ligands in cytotoxicity assays (page 2, left column, para 2, lines 1-9).
Chen and Hoseini do not teach that the spontaneous lysis of recombinant SUP-B15 expressing a liquid tumor-associated antigen such as PD-L1, CD33, CD123 and CD20 is less than 20% in the presence of CAR-T or NK cells at an effector cell to recombinant cell ratio of 1 or less, however Hasenkamp teaches that SUP-B15 cells show less than 10% lysis in presence of NK cells at an effector cell to target cell ratio of 1 or less (Figure 1B)(required for claim 1, 10-11 and 21). Further, Hasenkamp teaches that SUP-B15 is resistant to NK cell targeting by stating that “We conclude that SupB15 escapes from recognition as NK cell target because of appropriate inhibitory KIR ligand expression and by lacking ligands to stimulate NK cell receptors” (page 448). Therefore, Hasenkamp teaches that SUP-B15 shows low (less than 10%) background/ spontaneous lysis in the presence of NK cells since SUP-B15 lack the transmembrane antigen required by NK-cells for targeting.
Therefore, it would be obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to substitute the VE-Cadherin transmembrane antigen of Chen with the liquid tumor associated antigens of Hoseini to yield a predictable result of a recombinant SUP-B15 expressing liquid tumor associated antigen. An ordinary artisan would be motivated to perform this substitution so they can use a leukemia-specific cell line, such as SUP-B15 taught by Chen, in cytotoxicity assay, such as that of Hosseini, to test the specificity of newly developed CAR-NK or CAR-T cells. An ordinary artisan would reasonably expect that the recombinant SUP-B15 expressing a liquid tumor associated antigens produced by combination of Chen and Uherek would exhibit less than 10% spontaneous lysis because Hasenkamp teaches that SUP-B15 cells are resistant to NK cell targeting and therefore for NK cells to lyse SUP-B15, NK cells must express a receptor (such as CAR) that can specifically bind an antigen expressed on the SUP-B15 cell.
Claims 6 and 7 are rejected under 35 U.S.C. 103 as being unpatentable over Chen et al (Stromal cells attenuate the cytotoxicity of imatinib on Philadelphia chromosome-positive leukemia cells by up-regulating the VE-cadherin/β-catenin signal. Leukemia Research, Volume 38, October 2014; reference of record) and Uherek et al (Retargeting of natural killer–cell cytolytic activity to ErbB2-expressing cancer cells results in efficient and selective tumor cell destruction. Blood, Volume 100, August 2002; reference of record) in view of Hasenkamp et al (Resistance Against Natural Killer Cell Cytotoxicity: Analysis of Mechanisms. Scandinavian Journal of Immunology, Volume 64, 2006; reference of record) as applied to claims 1 above, further in view of Boissel et al (Comparison of mRNA and lentiviral based transfection of natural killer cells with chimeric antigen receptors recognizing lymphoid antigens. Leukemia & Lymphoma, Volume 53, May 2012).
As noted above, owing to the teachings of Hasenkamp, Chen and Uherek teach the recombinant target cell of claim 1.Chen also teaches that the recombinant human target cell comprises a recombinant nucleic acid wherein the recombinant nucleic acid is a plasmid.
Chen does not teach a lentiviral vector or recombinant RNA as a recombinant nucleic acid. Boissel teaches protocols for using mRNA or lentiviral vector as recombinant nucleic acids to transfect cells. Boissel teaches that although mRNA and lentiviral vectors have distinct advantages and disadvantages (Introduction, para 3, 4), both result in expression of transgene (Figure 1) and suggest their use based on the application (Abstract; Discussion, last para).
Therefore, it would be obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to substitute the plasmid recombinant nucleic acid of Chen with the lentiviral or recombinant RNA of Boissel to yield the predictable result of a recombinant cell that expresses an exogenous transmembrane protein. An ordinary artisan would choose the method of transgene delivery (plasmid, lentiviral or RNA) based on their specific application and/or experimental needs and would reasonably expect to be able to deliver the transgene to a cell by any of these routine methods each of which have been described in Chen and Boissel.
Rejection of Claim 12 under 35 U.S.C. 103 as being unpatentable over Uherek, or in the alternative over Muller as applied to claim 1 above, further in view of Morvan et al (NK cells and cancer: you can teach innate cells new tricks. Nature Reviews: Cancer, Volume 16, December 2015) is now moot because claim is cancelled.
Double Patenting
A rejection based on double patenting of the “same invention” type finds its support in the language of 35 U.S.C. 101 which states that “whoever invents or discovers any new and useful process... may obtain a patent therefor...” (Emphasis added). Thus, the term “same invention,” in this context, means an invention drawn to identical subject matter. See Miller v. Eagle Mfg. Co., 151 U.S. 186 (1894); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Ockert, 245 F.2d 467, 114 USPQ 330 (CCPA 1957).
A statutory type (35 U.S.C. 101) double patenting rejection can be overcome by canceling or amending the claims that are directed to the same invention so they are no longer coextensive in scope. The filing of a terminal disclaimer cannot overcome a double patenting rejection based upon 35 U.S.C. 101.
Applicant is advised that should claim 5 be found allowable, claim 21 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Response to Arguments
Applicant's arguments filed 1/30/2024 regarding the U.S.C. 103 rejection of claims 1, 3, 5, 8-11 (page 6, section c) have been fully considered but they are not persuasive. Applicant argues that Chen and Uherek, in combination, do “not teach or make obvious a recombinant SUP-B15 target cells that express a tumor antigen, such as PD-L1, CD33, CD123, HER-2, or CD20 (these antigens are normally not expressed in SUP-B 15 cells), and wherein the SUP-B 15 cell exhibits equal or less than 20% spontaneous lysis in the presence of a CAR-T or an NK cell at an effector cell to recombinant human target cell ratio of 1 or less” (page 7, para 2) and Hasenkamp does not rectify this deficiency because “Hasenkamp teaches that SUP-B 15 is not a suitable cell line for NK cells” (page 7, para 5). This is unpersuasive because, as noted by the applicant, Hasenkamp teaches that “SupB15 escapes from recognition as NK cell target” (page 7, para 4) because SUP-B15 do not express the ligand required for NK-cell recognition. Figure 1B shows that NK cell do not effectively lyse SupB15 (black bars, about 5% lysis) however when SupB15 are exposed to NK cell granules, lysis increases by about 6-folds (white bar, about 30% lysis). This shows that SupB15 do lyse in presence of the NK cell granules but NK cells do not recognize the SUP-B15 and thus do not release the granules. Uherek teaches that unless both NK cells and target cells are modified to express matching ligands and CARs respectively, background lysis of target cells is below 10%. Taken together, Hasenkamp and Uherek teach that Sup-B15 would show low back ground/spontaneous lysis in the presence of NK cells and, when NK cells and Sup-B15 are modified to express matching ligands and CARs, this would result in significantly increased (targeted) lysis over background lysis because Sup-B15 are susceptible to NK cell granules (see 6-fold increase in Figure 1B). An ordinary artisan would recognize this property of SUP-B15 cells could serve them as an ideal target cell to investigate CAR-NK cell being developed for therapeutic applications. Applicant also argue that “Hasenkamp does not talk about spontaneous lysis anywhere in their paper, and certainly does not make a distinction between spontaneous lysis and targeted lysis” (page 7, para 6). This is unpersuasive because Hasenkamp teaches less than 10% lysis of SUP-B15 in the presence of an NK cell that is not expressing a SUP-B15-specific receptor. Spontaneous or background lysis is non-targeted lysis. See remarks filed 1/30/2024, page 4, last para: “spontaneous lysis by the effector cell versus the CAR or ADCC mediated cytotoxicity” (emphasis added). In other words, spontaneous lysis is the lysis of a “target” cell observed in the presence of an effector immune cell that is not designed to target the “target cell” i.e. non-CAR/non-ADCC.
Applicant's arguments filed 1/30/2024 regarding the U.S.C. 103 rejection of claims 1, 4, 5-7, 8-11 (page 7, section d; page 8, section e) have been fully considered but they are not persuasive. Applicants arguments are same the arguments presented for claims 1, 3, 5, 8-11 (page 6, section c) that are discussed above. These arguments are unpersuasive because of the reasons presented above.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MATASHA DHAR whose telephone number is (571)272-1680. The examiner can normally be reached M-F 8am-4pm (EST).
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/MATASHA DHAR/Examiner, Art Unit 1632 /VALARIE E BERTOGLIO/Primary Examiner, Art Unit 1632
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