DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
The claim listing filed April 27, 2023 is pending.
Claims 1, 14, and 26 are independent claims.
Claims 1-26 are pending.
Claims 1, 14, and 26 are independent claims.
Oath/Declaration
The declaration under 37 CFR 1.130(a) filed on February 11, 2026 is sufficient to overcome any potential rejections of claims 1-26 under 35 U.S.C. 102 and/or 103 based on Braverman et al. “Increasing AMPK activity supports enhanced oxidative metabolism, proliferation, and in vitro recovery of human CD4 T cells.” J. Immunol., May 1, 2020, 204(1 Supplement), 240.2.
The declaration states that the Braverman publication describes the work of the inventors Craig Byersdorfer and Erica Braverman as it relates to the claimed methods for making T cells and T cell populations and methods of increasing an immune response relating to T cells having an increased level of an AMPKγ2 polypeptide. Thus, Craig Byersdorfer and Erica Braverman invented the potential prior art subject matter in the Braverman Article.
The declaration further states that Andrea Dobbs, Darlene Monlish, and Rebecca Audrey Brown, who are listed as a co-authors of the Braverman Article, are not inventors of the claimed subject matter. None of these individuals contributed to the conception of the claimed subject matter. They were working under the direction of Craig Byersdorfer and/or Erica Braverman or were collaborators that provided technical support or materials.
Election/Restrictions
Applicant’s election without traverse of Group II (claims 14-24, drawn to a method of increasing an immune response in a subject comprising administering to the subject a therapeutically effective amount of a T cell having an increased level of an AMPKy2 polypeptide as compared to a control); and the species of CAR T cell in the reply filed February 11, 2026 is acknowledged.
It is noted that the Examiner inadvertently left claim 26 out of the restriction requirement mailed 12/09/2025. Claim 26 is drawn to a method of making a population of T cells comprising increasing a level of a AMPKy2 polypeptide in the T cells as compared to a control T cell population and is therefore included in Group I.
The Examiner also inadvertently included claim 25 in Group I in the restriction requirement mailed 12/09/2025. Claim 25 is drawn to the method of claim 14 and is therefore included in Group II.
Upon further consideration in view of the declaration under 37 CFR 1.130(a) filed on February 11, 2026 as noted above, the restriction requirement with respect to Groups I and II lacking unity in view of Braverman et al. 2020 in the office action mailed on 10/09/2025 is withdrawn.
In view of the withdrawal of the restriction requirement, applicant(s) are advised that if any claim presented in a divisional application is anticipated by, or includes all the limitations of, a claim that is allowable in the present application, such claim may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application. Once the restriction requirement is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable. See In re Ziegler, 443 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971). See also MPEP § 804.01.
Therefore, claims 1-13 and 26 and all species of T cells are rejoined. Claims 1-26 are currently under consideration.
Claim Rejections - 35 USC § 112
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.
Claims 15 and 17 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 15 recites “wherein the AMPKy2 polypeptide comprises a sequence at least 95% identical to SEQ ID NO: 1” in lines 1 and 2. However, claim 15 is dependent on claim 14 which recites that “the AMPKy2 polypeptide comprises SEQ ID NO:1.” Therefore, claim 15 broadens the genus of AMPKy2 polypeptides of claim 14. Thus, claim 15 is not further limiting and is actually claiming more than what is claimed in claim 14.
Claim 17 recites “wherein the polynucleotide sequence is at least 90% identical to SEQ ID NO: 2” in lines 1 and 2. However, claim 17 is dependent on claims 14 and 16 which recites that “the AMPKy2 polypeptide comprises SEQ ID NO:1.” Therefore, claim 17 broadens the genus of AMPKy2 polypeptides of claim 14 because the recited variability permitted for the polynucleotide may encode AMPKy2 polypeptides that do not comprise SEQ ID NO: 1. Thus, claim 17 is not further limiting and is actually claiming more than what is claimed in claim 14 and 16.
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
Indefinite language
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.
Claims 1-26 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.
Claims 1, 8, 12-14, 21, 25, and 26 recite the terms “a control,” “the control,” “a control T cell population,” and/or “the control T cell population” which are meant to be compared to the T cell having an increased level of an AMPKy2 polypeptide. However, it is unclear what the control is meant to be, especially in relation the T cell having an increased level of an AMPKy2 polypeptide. Therefore, the term renders the instant claims indefinite.
Amending claims 1, 8, 12-14, 21, 25, and 26 to recite “a/the control T cell expressing an endogenous level of the AMPKy2 polypeptide” would obviate this part of the rejection.
Claims 3 recites “wherein the method comprises introducing a polynucleotide sequence encoding the AMPKy2 polypeptide into the T cell” in lines 1-3. It is unclear what order the steps of this claim are meant to occur in. For example, it is unclear if the introduction of the polynucleotide sequence encoding the AMPKy2 polypeptide into the T cell happens before or after the level of the AMPKy2 polypeptide is increased. Therefore, claim 3 is indefinite.
Amending claim 3 to recites “wherein the method comprises introducing a polynucleotide sequence encoding the AMPKy2 polypeptide into the T cell prior to increasing the level of the AMPKy2 polypeptide in the T cell” would obviate this part of the rejection.
Claims 6 and 19 recite “further comprising culturing the T cell in the presence of IL-2” in lines 1 and 2. Similar to the rejection to claim 3 above, it is unclear what order the steps of this claim are meant to occur in. For example, it is unclear if the culturing of the T cell in the presence of IL-2 happens before or after the level of the AMPKy2 polypeptide is increased. Therefore, claims 6 and 19 is indefinite.
Amending claims 3 and 19 to recite “further comprising culturing the T cell in the presence of IL-2 after increasing the level of the AMPKy2 polypeptide in the T cell ” would obviate this part of the rejection.
Claims 4 and 17 recites “wherein the polynucleotide sequence is at least 90% identical to SEQ ID NO: 2” in lines 1 and 2. However, claim 4 is dependent on claims 1 and 3 and claim 17 is dependent on claims 14 and 16 which recite that “the AMPKy2 polypeptide comprises SEQ ID NO:1.” Given the variability permitted for the polynucleotide that encodes the AMPKy2 polypeptide, claims 4 and 17 include species of AMPKy2 polypeptides that do not comprise SEQ ID NO: 1 which would lack antecedent basis. Thus, claims 4 and 17 are indefinite.
Amending claims 4 and 17 to recite that the polynucleotide sequence is SEQ ID NO: 2 would obviate this part of the rejection.
Claim 15 recites “wherein the AMPKy2 polypeptide comprises a sequence at least 95% identical to SEQ ID NO: 1” in lines 1 and 2. However, claim 15 is dependent on claim 14 which recites that “the AMPKy2 polypeptide comprises SEQ ID NO:1.” Therefore, claim 15 includes species of AMPKy2 polypeptides that lack antecedent basis because they do not comprise SEQ ID NO: 1. Thus, claim 15 is indefinite.
Canceling claim 15 or amending claim 14 to recite that the AMPKy2 polypeptide comprises a sequence at least 95% identical to SEQ ID NO: 1 and amending claim 15 to recite that the AMPKy2 polypeptide comprises SEQ ID NO:1 would obviate this part of the rejection.
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.
Enablement
Claims 3 and 14-25 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph.
Regarding claim 3, the specification, while being enabling for a method of making a T cell comprising increasing a level of an AMPKy2 polypeptide in the T cell as compared to a control by introducing a vector comprising a polynucleotide sequence encoding the AMPKy2 polypeptide into the T cell; does not reasonably provide enablement for a method of making a T cell comprising increasing a level of an AMPKy2 polypeptide in the T cell as compared to a control by introducing a polynucleotide sequence encoding the AMPKy2 polypeptide into the T cell
Regarding claims 14-25, the specification, while being enabling for a method of increasing a T cell immune response in a subject comprising administering to the subject a therapeutically effective amount of a T cell having an increased level of an AMPKy2 polypeptide; does not reasonably provide enablement for a method of increasing any immune response in a subject comprising administering to the subject a therapeutically effective amount of a T cell having an increased level of an AMPKy2 polypeptide.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
The factors considered in determining whether a disclosure would require undue experimentation include:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In re Wands, 8 USPQ2d, 1400 (CAFC 1988) and MPEP § 2164.01.
Nature of the invention/Breadth of the claims
Claim 3 is drawn to a method of making a T cell comprising increasing a level of an AMPKy2 polypeptide in the T cell as compared to a control, wherein the AMPKy2 polypeptide comprises SEQ ID NO:1, and wherein the T cell having the increased level of the AMPKy2 polypeptide has an increased oxidative metabolism as compared to the control, wherein the method comprises introducing a polynucleotide sequence encoding the AMPKy2 polypeptide into the T cell.
Claims 14-25 are drawn to a method of increasing an immune response in a subject comprising administering to the subject a therapeutically effective amount of a T cell having an increased level of an AMPKy2 polypeptide as compared to a control, wherein the AMPKy2 polypeptide comprises SEQ ID NO:1.
State of the prior art/Predictability of the art
Regarding claim 3, the art teaches that recombinant proteins are produced by first generating a plasmid by cloning the DNA encoding the protein into parent plasmids or vectors for expression and purification from a variety of cells (e.g. see DeLuca et al. STAR Protocols. 2022, 3, 101915, 1-17; page 1, paragraph under “Before you begin”). Many plasmids or vectors have been generated for the purpose of expressing and purifying full-length proteins from human cells, however, the protein sequences can be cloned into any plasmid appropriate for expression of high levels of recombinant protein in mammalian cells (e.g. see page 1, paragraph under “Before you begin”). Any plasmid designed for a high level of protein expression in mammalian cells (e.g., driven by a CMV promotor) can be used to generate the parent heavy and light chain plasmids or vectors (e.g. see note on page 8).
Thus, the art teaches that in order for the protein to be produced (or expressed) by a host cell, the DNA encoding the protein needs to be inserted into an appropriate plasmid backbone that has all of the elements required for protein expression (i.e. promoter, origin of replication, selectable marker). This plasmid can then be used to transform a host cell for protein expression.
Regarding claims 14-25, Braverman et al. 2024 (J. Biol. Chem. 300(1), 105488, 1-14) teach that increasing AMPK activity in primary human T cells, through lentiviral-driven overexpression of AMPKγ2, upregulates oxidative metabolism, decreases cellular differentiation, and improves in vitro expansion (e.g. see page 10, right column, second paragraph). Braverman et al. also teach that, further, the resulting T cells demonstrate a decreased likelihood of developing into Th2 cells, with promotion of an inflammatory phenotype in bulk and conventional Th subsets and increased suppressive capacity when activity is driven specifically in Treg. Braverman et al. also teach that, together, these characteristics provide an attractive method to improve the function of current adoptive cellular therapies and work is ongoing to assess the potential contribution of this modification to multiple T cell–based approaches in vivo (e.g. see page 10, right column, second paragraph).
Thus, the art ultimately teaches that the overexpression of AMPKγ2 in T cells increases the immune response of the T cells specifically.
Working examples/Guidance in the specification
Regarding claim 3, the Applicant has only disclosed that the method of making a T cell comprising increasing a level of an AMPKy2 polypeptide in the T cell is done by introducing a lentiviral vector comprising a polynucleotide encoding the AMPKy2 polypeptide, not by a naked polynucleotide (e.g. see page 32, lines 23-30).
Regarding claims 14-25, the Applicant discloses that T cells transduced with wild type and truncated AMPKy2 (SEQ ID NO: 1) exhibited increased growth in comparison with empty construct-transduced T cells (Fig. 5 and Fig. 14A-C) (e.g. see page 33, lines 6-11). The Applicant also discloses that there was an increase in CD4+ T cell percentages following AMPKy2-transduction (Fig. 6) (e.g. see page 33, lines 12-18). Consistent with the increased percentages of CD4+ T cells, an increase in CD4+ T cell counts was also observed (Fig. 7) (e.g. see page 33, lines 12-18). The Applicant also discloses that AMPKy2-transduced T cells are less differentiated as measured by multiple parameters (e.g. see page 33, lines 19-24).
The Applicant also discloses that AMPKy2-transduced T cells show increased mitochondrial metabolism, spare respiratory capacity following stimulation through the T cell receptor, and importantly an increase in extracellular acidification rates, indicative of an increase in glycolysis, in AMPKy2-transduced that were stimulated prior to analysis (e.g. see page 33, line 25 – page 34, line 5). The Applicant also discloses that AMPKy2 transduction does not increase T cell exhaustion (e.g. see page 34, lines 6-15).
Thus, the Applicant ultimately discloses that the overexpression of AMPKγ2 in T cells increases the immune response of the T cells specifically.
Amount of experimentation necessary
Regarding claim 3, the instant specification has only disclosed that the method of making a T cell comprising increasing a level of an AMPKy2 polypeptide in the T cell is done by introducing a lentiviral vector comprising a polynucleotide encoding the AMPKy2 polypeptide, not by a naked polynucleotide. There is insufficient objective evidence that the specific method disclosed in the specification can be extrapolated to provide guidance and direction for use any polynucleotide sequence to transform a host cell for production of the AMPKy2 polypeptide.
As it is known in the art, producing a protein generally involves culturing a cell that has been transformed with a DNA plasmid comprising the protein gene and critical elements required for protein expression (i.e. promoter, origin of replication, selectable marker). These plasmids or vectors are optimized for independent replication, controlled expression, and high yield. While the Applicant has disclosed how to make a T cell with an increased level of AMPKy2 polypeptide by introducing a vector comprising a polynucleotide encoding the AMPKy2 polypeptide to the T cell, the Applicant has not disclosed how to make T cells with an increased level of AMPKy2 polypeptide by introducing any polynucleotide encoding the AMPKy2 polypeptide to the T cell.
Thus, based on the content of the disclosure in view of the prior art, a skilled artisan, through extensive trial-and-error experimentation, would have to introduce any polynucleotide encoding the AMPKy2 polypeptide to the T cell in order to increase the level of the AMPKy2 polypeptide in the T cell with a reasonable expectation of success. This quantity of experimentation goes beyond what is considered “a reasonable degree of experimentation” and constitutes undue further experimentation in order to enable a skilled artisan to use the method of making a T cell comprising increasing a level of an AMPKy2 polypeptide in the T cell as compared to a control for the breadth of what is claimed.
Regarding claims 14-25, the instant specification has only disclosed that the overexpression of AMPKγ2 in T cells increases the immune response of the T cells specifically. However, the claims are not limited to a method of increasing a T cell immune response but are instead drawn to a method of increasing any immune response.
Therefore, there is insufficient objective evidence that the disclosed AMPKγ2-overexpressing T cells can be extrapolated to provide guidance and direction for how to make and/or use a method of increasing any immune response in a subject comprising administering to the subject a therapeutically effective amount of a T cell having an increased level of an AMPKy2 polypeptide as compared to a control, wherein the AMPKy2 polypeptide comprises SEQ ID NO:1. Thus, a skilled artisan, through extensive trial-and-error experimentation, would have to make a AMPKγ2-overexpressing T cell and use it to increase any immune response, including those beyond that of a T cell immune response. This quantity of experimentation goes beyond what is considered “a reasonable degree of experimentation” and constitutes undue further experimentation in order to enable the method of increasing an immune response in a subject the breadth of what is claimed.
Thus, the specification does not enable one of ordinary skill in the art to make and/or use what is claimed and therefore claims 3 and 14-25 are rejected under 35 U.S.C. 112(a) enablement.
Amending claim 3 to recites “wherein the method comprises introducing a vector comprising a polynucleotide sequence encoding the AMPKy2 polypeptide into the T cell” and amending claim 14 to recite “A method of increasing a T cell immune response in a subject” would obviate this part of the rejection.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Grace H. Lunde whose telephone number is (703)756-1851. The examiner can normally be reached Monday - Thursday 6:00 a.m. - 3:00 p.m. (EST).
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu can be reached at (571) 272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/GRACE H LUNDE/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641