DETAILED ACTION
1. Claims 1-19, and 24 are currently pending and under examination in this action.
Notice of Pre-AIA or AIA Status
2. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
3. Claims 1-19 and 24 claim benefit to provisional application 63/107,027 filed on 10/29/2020 and PCT/JP2021/040069 filed on 10/29/2021. The applications were reviewed for relevant subject matter and claims 1-2, 4-7, 9, 11-12, and 15-19 were disclosed through the provisional application 63/107,027. However, claims 3, 8, 10, 13-14, and 24 all cited limitations not disclosed in the provisional application but disclosed in the PCT application. Specifically, claims 3, 10, and 13 all cite CD19 and CD7 as cell possible cell surface antigens but are not disclosed as possible selections in the provisional application, either in the claims or in the specification. Claims 8, 14, and 24 cite the agent for the treatment or prevention of certain cancers including B-ALL, T-ALL, MPAL, and CML but these cancers are not disclosed in the claims or the specification of 63/107,027 but is disclosed in the PCT application.
Therefore, the following priority and effective filing dates are being given according the claim groups listed below:
Claims 1-2, 4-7, 9, 11-12, and 15-19 priority granted to 63/107,027 with the effective filing date 10/29/2020;
Claims 3, 8, 10, 13-14, and 24 priority granted to PCT/JP2021/040069 with the effective filing date 10/29/2021.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
4. Claims 1-19, and 24 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
The claims are drawn to a cell co-expressing a chimeric antigen receptor (CAR) protein and a CXCL12 receptor protein on the cell membrane.
Dependent claim 3, further recites the chimeric antigen receptor (CAR) protein targets a cell surface antigen selected from among CD25 (IL-2 receptor alpha chain), CD19, and CD7.
Dependent claims 9-11 further recite the cell of claim 1 introducing a first polynucleotide encoding a CAR protein and a second polynucleotide encoding a CXCL12 receptor protein into a cell, wherein the CAR targets CD25, CD19, or CD7.
Dependent claims 12-19 and 24 require the cell co-expressing a CXCL12 receptor protein and CAR protein targeting CD25, CD19, or CD7 to treat/prevent relapse of a neoplastic disease.
Thus, the claims encompass a vast genus of CXCL12 receptor-expressing cells that additionally expressing a CAR of unknown sequence that functions to bind to CD25, CD19, or CD7, and treat/prevent relapse of a neoplastic disease.
The instant specification discloses two separate constructs that were made: a CXCR4-expressing CD25 CAR-T cell (See Example 1 and 2 pg. 34-36 [0107]-[0114]) and a CXCR4-expressing CD19 CAR-T cell (See Examples 3 and 4, pg. 36-37 [0115]-[0120]). However, the specification does not disclose the sequences of the CARs that function to bind CD19 or CD25. The instant specification does not disclose a single exemplary CAR sequence that functions to bind CD7.
The instant specification further discloses the anti-IL2RA/CD25 protein single chain variable fragment (scFv) and intracellular CD3z and CD137 (4-1BB) signaling domains for preparing the CD25 CAR protein were designed according to Figure 2A and Michael C. Milone, et al., 2009, Mol. Therapy, 17(8): 1453-64, which was incorporated by reference (See Reference Example 2, pg. 32, [0098]). A review of Milone 2009 reveals a CAR construct that binds to CD19 and not to CD25. Further, the sequences of the CAR binding to CD19, CD25, or CD7 are essential material for making and using the cells as claimed. MPEP 608.01(p) states: “For the written description requirement, an applicant’s specification must reasonably convey to those skilled in the art that the applicant was in possession of the claimed invention as of the date of invention”. MPEP 608.01(p) further defines the conditions for proper incorporation by reference under 37 CFR 1.57:
37 CFR 1.57 states (bold emphasis added):
(c)
“Essential material” may be incorporated by reference, but only by way of an
incorporation by reference to a U.S. patent or U.S. patent application
publication, which patent or patent application publication does not itself
incorporate such essential material by reference. “Essential material” is material
that is necessary to:
(1) Provide a written description of the claimed 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 set forth the
best mode contemplated by the inventor of carrying out the invention as
required by the first paragraph of 35 U.S.C. 112;
(2) Describe the claimed invention in terms that particularly point out and
distinctly claim the invention as required by the second paragraph of 35
U.S.C. 112; or
(3) Describe the structure, material, or acts that correspond to a claimed means
or step for performing a specified function as required by the sixth paragraph of
35 U.S.C. 112.
Thus, the incorporation by reference of non-patent literature to describe essential material is improper.
Thus, the instant specification discloses making two CXCR4-expressing CAR-T cell constructs, which bind to CD25 and CD19, but does not disclose their sequences. The specification states that it discloses the structure of the anti-CD25 binding portion of the CD25 CAR protein, but by an improper incorporation by reference, and to a reference that appears to describe a CD19 CAR.
The specification fails to disclose a single exemplary sequence structure of: (i) an anti-CD19 binding region for a CD19 CAR protein, (ii) an anti-CD25 binding region for a CD25 CAR protein; and (iii) an anti-CD7 binding region for a CD7 CAR protein.
To provide adequate written description and evidence of possession of the claimed CAR cell genus, the instant specification can structurally describe representative CARs that function to bind CD25, CD19, or CD7, and treat or prevent relapse of neoplastic diseases, or describe structural features common to the members of the genus, which features constitute a substantial portion of the genus. Alternatively, the specification can show that the claimed invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics (see University of California v. Eli Lilly and Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997) and Enzo Biochem, Inc. V. Gen-Probe Inc.). A disclosure that does not adequately describe a product itself logically cannot adequately describe a method of using that product.
In this case, the only factor recited in the claims is a “CAR protein”, a recitation of CAR function to bind CD19, CD25, or CD7, and a recitation of CAR cell function to treat/prevent relapse of a neoplastic disease. The instant specification fails to describe representative CARs and cells comprising them that function as claimed, or which features constitute a substantial portion of the genus, because the instant specification fails to disclose any CAR sequences that function as claimed in the CAR cell. Therefore, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus of CARs required to make and use the cells as claimed.
With regards to claim 3, the claimed invention only recites the function of the CAR protein targeting a CD25 (IL-2 receptor alpha chain), CD19, and CD7 with no claimed sequence structure. The instant specification fails to properly disclose structural features common to the members of the CD25 CAR, CD19 CAR, or CD7 CAR genus, which features constitute a substantial portion of the genus because the specification fails to disclose representative CD25 CAR, CD19 CAR, or CD7 CAR sequences that function as claimed. A definition by function does not suffice to define the genus because it is only an indication of what the CAR protein does, not what it is. The specification fails to describe a representative number of CAR sequences for the genus of CD25 CAR, CD19 CAR, and CD7 CAR variants as claimed. Therefore, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus required to make the CD25, CD19, and CD7 CAR proteins as claimed.
With regards to claims 9-11, the claimed invention only recites a method of creating the CXCL12 receptor expressing CAR cell of claim 1 by introducing a polynucleotide sequence for a CAR protein targeting CD25, CD19, and CD7. The instant specification fails to properly disclose structural features common to the members of the CD25 CAR, CD19 CAR, and CD7 CAR genus, which features constitute a substantial portion of the genus because the specification fails to disclose representative CD25 CAR, CD19 CAR, and CD7 CAR polynucleotide sequences. A definition by function does not suffice to define the genus because it is only an indication of what the CAR protein does, not what it is. The specification fails to describe a representative number of CAR polynucleotide sequences for the genus of CD25 CAR, CD19 CAR, and CD7 CARs as claimed. Therefore, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus required to make the polynucleotide encoding the CD25, CD19, and CD7 CAR proteins as claimed.
Although Applicants may argue that it is possible to screen for CARs that bind CD25, CD19, and CD7 and function as claimed, the court found in (Rochester v. Searle, 358 F.3d 916, Fed Cir., 2004) that screening assays are not sufficient to provide adequate written description for an invention because they are merely a wish or plan for obtaining the claimed chemical invention. “As we held in Lilly, “[a]n 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.” 119 F.3d at 1566 (quoting Fiers, 984 F.2d at 1171). For reasons stated above, that requirement applies just as well to non-DNA (or RNA) chemical inventions.” Knowledge of screening methods provides no information about the structure of any future CARs yet to be discovered that may function as claimed. The CD19, CD25, and CD7 antigens provide no information about the structure of CAR that binds to them.
Given the lack of representative examples to support the full scope of the claimed CARs comprised by the cells, and lack of proper sequence disclosure, the present claims lack written description. Thus, the specification does not provide an adequate written description of CARs that bind CD25, CD19, and CD7 that are required to practice the claimed invention.
5. Claims 12-19 and 24 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.
Claims 12 and 24 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of treatment of relapse of a neoplastic disease in a subject by administering a cell co-expressing a CAR protein targeting CD25 and a CXCL12 receptor protein, does not reasonably provide enablement for a method of preventing relapse of a neoplasm. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
The factors to be considered in determining whether undue experimentation is required are summarized In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988). The court in Wands states: "Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is 'undue,' not 'experimentation.' " (Wands, 8 USPQ2d 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. "Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations." (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount or direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims.
The claims as currently constituted encompass methods of preventing relapse of a neoplastic disease.
The instant specification discloses treating a mouse model of CD19-expressing Burkitt's lymphoma by administering a CXCR4-expressing CD19 CAR-T cell, reducing the number of CD19 lymphoma cells in the bone marrow and liver compared to untreated controls (Example 4; Figure 14). The instant specification does not demonstrate that the claimed CAR-expressing immune cells prevent relapse of a neoplastic disease. (See Examples pgs. 34-37).
A search of relevant art does not support that CAR T cells prevent cancer. For example, WO 2018/140725, Posey et al, cited below, demonstrates that CAR T cells comprising a mutated CD28 YMNM motif treated established cancer xenografts but does not demonstrate prevention of cancer (Examples).
One cannot extrapolate the disclosure of the specification to the scope of the claims because the specification lacks the critical steps necessary in presenting some type of predictable response in a population of hosts deemed necessary to prevent the relapse of cancer. Reasonable guidance with respect to preventing any cancer relies on quantitative analysis from defined populations which have been successfully pre-screened and are predisposed to particular types of cancer or have had cancer. The essential element towards the validation of a preventive therapeutic is the ability to test the drug on subjects monitored in advance of clinical cancer and Iink those results with subsequent histological confirmation of the presence or absence of disease. This irrefutable link between antecedent drug and subsequent knowledge of the prevention of the disease is the essence of a valid preventive agent. All of this underscores the criticality of providing workable examples which are not disclosed in the specification. A high quantity of experimentation would be required to determine if and what cancers the claimed CAR-expressing cell could prevent.
Reasonable correlation must exist between the scope of the claims and scope of enablement set forth, and it cannot be reasonably predicted that the claimed cell comprising the claimed CAR will predictably function to prevent the relapse of cancer as claimed.
Therefore, in view of the state of the art, the quantity of experimentation necessary, the breadth of the claims, lack of guidance in the specification, and the absence of working examples, it would require undue experimentation for one skilled in the art to practice the invention as broadly claimed.
Examiner suggests amending claim(s) 12 and 24 to delete the term prevention.
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. Claim 6 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Claim 6 recites: “The agent according to claim 5, which is used in combination with a further anti-tumor agent and/or anti-tumor therapy”. The phrase “which is used” renders the claim indefinite because it is unclear if it is an acti method/process step or an intended use of the product. The metes and bounds of the claimed invention cannot be determined.
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.
7. Claim 13 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 13 recites, ”The method according to claim 12, wherein the CAR protein targets a cell surface antigen selected from among CD25 (IL-2 receptor alpha chain), CD19, and CD7. Claim 12 recites the CAR protein targeting CD25 alone. Therefore, claim 13 does not further limit the subject matter but improperly broadens the claimed subject matter. 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 § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
AIA § 33(a) reads as follows:
(a) LIMITATION.—Notwithstanding any other provision of law, no patent may issue on a claim directed to or encompassing a human organism.
8. Claims 1-3, 5-8 and 24 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a human organism. Notwithstanding any other provision of law, no patent may issue on a claim directed to or encompassing a human organism.
Claims 1-3 are rejected under 35 U.S.C. 101 and AIA § 33(a) as being directed to or encompassing a human organism. The claims read on cells found in intact mammals, including humans that receive nucleic acids encoding the claimed proteins. Claim 7 cites “a pharmaceutically acceptable carrier” this encompasses a human organism with water. Claim 24 further cites an intended use of the human with water. See also Animals - Patentability, 1077 Off. Gaz. Pat. Office 24 (April 21, 1987) (indicating that human organisms are excluded from the scope of patentable subject matter under 35 U.S.C. 101).
Claims 5-6, and 8 are further rejected based on their dependency on rejected claims and their inability to overcome a 35 U.S.C. 101 rejection.
It is suggested that applicant amend claim to recite, “an isolated cell” or “an isolated T cell” to overcome this rejection.
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.
9. Claims 1-3, 5-7, and 9-11 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Jamali (Front. Immunol., Aug. 28, 2020, 11:2028; as cited in the IDS from 4/28/2023) as evidenced by Mokhtari (Oncotarget, 2017, 8(23):38022-38043).
In regard to claim 1, Jamali discloses “A cell co-expressing a chimeric antigen receptor (CAR) protein and a CXCL12 receptor protein on the cell membrane.” (See Jamali pg.2, column 2, paragraph 2, lines 6-8).
In regard to claim 2, Jamali discloses the limitations of claim 1 as discussed above. Jamali further discloses “the CXCL12 receptor is CXCR4.” (See Jamali, pg. 2, column 2, paragraph 2, lines 6-8).
In regard to claim 3, Jamali discloses the limitations of claim 1 as discussed above. Jamali further discloses a chimeric antigen receptor (CAR) protein that targets a CD19 cell surface antigen. (See Jamali, pg. 2, column 2, paragraph 2, lines 6-8).
In regard to claim 5, Jamali discloses the limitations of claim 1 as discussed above. Jamali further discloses “an agent exhibiting anti-tumor activity, which comprises the cell according to claim 1.” (See Jamali, pg. 5, column 2, paragraph 3, lines 6-8; See also Fig. 3a).
In regard to claim 6, Jamali discloses the limitations of claim 1 and 5 as discussed above. Claim 6 further recites the agent from claim 5 used in combination with a further anti-tumor agent or anti-tumor therapy. As evidenced in Mokhtari, combination therapy is a cornerstone for cancer therapy. (See Mokhtari, abstract). Therefore, the limitations of claim 6 are known in the art.
In regard to claim 7, Jamali discloses the limitations of claim 1 as discussed above. Jamali further discloses “a pharmaceutical composition comprising the agent according to claim 5 and a pharmaceutically acceptable carrier.” (See Jamali, pg. 3, column 2, paragraph 5, lines 2-5).
In regard to claim 9, Jamali discloses the limitations of claim 1 as discussed above. Jamali further discloses a method for preparing the cell according to one of claims 1, which comprises introducing a first polynucleotide encoding a chimeric antigen receptor (CAR) protein and a second polynucleotide encoding a CXCL12 receptor protein into a cell. (See Jamali, pg. 3 NK Cell Transduction).
In regard to claim 10, Jamali discloses the limitations of claim 1 and 9 as discussed above. Jamali further discloses wherein the chimeric antigen receptor (CAR) protein targets CD19. (See Jamali, pg. 3 NK Cell Transduction).
In regard to claim 11, Jamali discloses the limitations of claim 1 and 9 as discussed above. Jamali further discloses wherein the first polynucleotide and the second polynucleotide are introduced into a cell by the same vector or separate vectors. (See Jamali, pg. 3 NK Cell Transduction).
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.
10. Claims 1-5, 7-8, and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Li (WO2020/135083 pub. 7/2/2020) in view of Arai (Biol. Blood Marrow Transplant, 2018, 24(S311):447, as cited in the IDS from 4/28/2023).
Li discloses a CAR-T cell with a chemokine receptor on the cell membrane for the use of trafficking CAR T cells to the site of difficult to reach solid tumors for anti-tumor treatment. (See Li, abstract and Fig. 4a). Li further discloses the CAR protein targeting a cell surface antigen of CD19. (See Li pg. 2, Summary, paragraph 7). Li further discloses a pharmaceutical composition comprising the agent of claim 5 and a pharmaceutically acceptable carrier (See Li, pg. 3, paragraph 5) for the treatment of tumors (See Li pg. 3 paragraph 7).
Li does not disclose the chemokine receptor being a CXCL12 receptor and specifically, CXCR4.
Arai teaches the use of enhanced expression of CXCR4 to target trafficking CAR-T therapeutics to the bone marrow. (See Arai, pg. S311, section 447, conclusion).
It would be obvious to a person of ordinary skill in the art prior to the effective filing date to combine the CAR-chemokine receptor of Li with the teaching of Arai to create the present claimed invention. CAR T-cell therapy has emerged as a promising treatment of choice for relapsing and refractory leukemias but has shown dismal outcomes in other hematologic malignancies and solid tumors. (See pg. 1, [0003-0004]). Li discloses a CAR T cell that uses a chemokine receptor to target a solid tumor for treatment. Further Arai teaches the use of CXCR4, CXCL12 receptor protein, was able to successfully guide a CAR T cell to the bone marrow, a main location of malignant hematology cells. Therefore, a person of ordinary skill in the art prior to the effective filing date would have been motivated to use the CXCR4 chemokine receptor of Arai within the design of Li to target malignant hematology cells in the bone marrow with a reasonable expectation of success.
11. Claims 12-16, and 18-19 are rejected under 35 U.S.C. 103 as being unpatentable over Jamali (Front. Immunol., Aug. 28, 2020, 11:2028; as cited in the IDS from 4/28/2023) and in view of Zhang et. al. (Blood Advances, May 26, 2020, 4(10), 2325-2338).
Jamali discloses a cell co-expressing a CD19 CAR and a CXCL12 receptor protein as discussed in section 9 under 35 U.S.C. 102. It should be noted that, based on the limitations of claim 13, it is assumed claim 12 was intended to encompass the administration of a CD19 and CD7 CAR cell.
Jamali does not disclose a method for treating or preventing the relapse of neoplastic diseases, such as B-ALL, in a subject comprising the administration of a single dose of the cell to the subject in a range of 104 to 109 cells per kg body weight.
Zhang discloses the administration of an anti-CD19 CAR T cell for the treatment of relapsed B-ALL (See Zhang, pg. 2326, column 1, lines 3-4) by administering the cell in a single dose between 1x105 to 10x105 CAR T cells per kg (See Zhang, pg. 2326, column 2, lines 16-17). Zhang further discloses the evaluation of therapeutic effects after the administration of the cell based on the indices of a decrease in tumor cells in the blood and bone marrow (See Zhang, pg. 2328, Table 3).
It would have been prima facie obvious to a person of ordinary skill in the art prior to the effective filing date to administer the cell co-expressing a CD19 CAR protein and CXCR4 chemokine receptor for the treatment of relapsed B ALL. One would have been motivated to and have a reasonable expectation of success to because certain cancers, such as AML, have been shown to have dismal clinical outcomes to traditional CAR-T cell therapy (See pg. 1, [0004]), Jamali teaches that the combination of the CXCR4 to a CAR cell increases the homing of CAR cells to the bone marrow, a tumor niche environment (See Jamali pg. 2, column 2, lines 21-24), and Zhang provides successful treatment of relapsed B-ALL expressing CD19 using anti-CD19 CAR T cells (See Zhang, pg.2336, column 2, lines 33-34). Therefore, a person of ordinary skill in the art would be motivated to administer a cell co-expressing a CD19 CAR protein and a CXCL12 chemokine receptor protein to treat a subject with a relapsed neoplastic disease with a reasonable expectation of success prior to the effective filing date.
12. Claim 17 is rejected under 35 U.S.C. 103 as being unpatentable over Jamali (Front. Immunol., Aug. 28, 2020, 11:2028; as cited in the IDS from 4/28/2023) and in view of Zhang et. al. (Blood Advances, May 26, 2020, 4(10), 2325-2338) as applied to claims 12-16 above; and in further in view of Vatsan. (Journal for Immunotherapy of Cancer 2013, 1:5).
Jamali and Zhang disclose the method of administering a cell expressing CD19 CAR and CXCL12 chemokine receptor to treat relapsed neoplastic disease as discussed above in section 11.
Jamali and Zhang does not disclose measuring the expression level of a target cell surface antigen in a tumor cell of the subject before the step of administering the cell.
Vatsan teaches that the clinical validation process for a therapeutic that includes a specific antigen target should include the measurement of the target antigen (See Vatsan, pgs. 12-13 “Co-development of Assays and Therapeutics”).
It would be prima facie obvious to a person of ordinary skill in the art prior to the effective filing date to combine the measurement of a target cell surface antigen prior to the administration of the cell expressing the target antigen for tracking the progression of the treatment efficacy. One would have been motivated to combine the pre-administration antigen measurement to the method of treatment because treating difficult cancers requires tracking the progress of the treatment and as Vatsan teaches when a therapy targets a specific antigen it is important to track that the therapy is effectively targeting the specific antigen. Therefore, it would have been obvious to a person of ordinary skill in the art prior to the effective filing date to add a step of measuring the cell surface antigen prior to the administration of a therapeutic targeting the specific cell surface antigen.
Conclusion
12. Claims 1-19 and 24 are rejected.
13. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LINDSAY DUNN whose telephone number is (571)272-5825. The examiner can normally be reached Monday-Friday 8-4:30.
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/LINDSAY DUNN/Examiner, Art Unit 1644
/Laura B Goddard/Primary Examiner, Art Unit 1642