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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on July 8, 2026 has been entered.
Detailed Action
This action is in response to the papers filed July 8, 2026.
Amendments
Applicant's response and amendments, filed July 8, 2026, is acknowledged. Applicant has cancelled Claims 2-21 and 23-24, and amended Claims 1 and 25.
Claims 1, 22, and 25 are pending and under consideration.
Priority
This application is a 371 of PCT/US2020/061107 filed on November 18, 2020. Applicant’s claim for the benefit of a prior-filed application provisional applications:
62/982,480 filed on February 27, 2020;
62/944,295 filed on December 5, 2019;
62/942,662 filed on December 2, 2019;
62/937,359 filed on November 19, 2019; and
62/937,028 filed on November 18, 2019,
under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
Information Disclosure Statement
Applicant has filed an Information Disclosure Statement on July 9, 2026 that has been considered.
The information disclosure statement filed July 9, 2026 fails to comply with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609 because 37 CFR 1.98(b) requires that each item of information in an IDS be identified properly. Each publication must be identified by publisher, author (if any), title, relevant pages of the publication, and date and place of publication. The date of publication supplied must include at least the month and year of publication, except that the year of publication (without the month) will be accepted if the applicant points out in the information disclosure statement that the year of publication is sufficiently earlier than the effective U.S. filing date and any foreign priority date so that the particular month of publication is not in issue.
See also MPEP 707.05(e) for electronic documents, including, but not limited to:
(D) reference to the unique Digital Object Identifier (DOI) number, or other unique identification number, if known.
NPL citations have been lined through for being defective of one or more requirements.
The signed and initialed PTO Forms 1449 are mailed with this action.
Claim Objections
1. The prior objections to Claims 1 and 5 are withdrawn in light of Applicant’s amendments to Claim 1, and cancellation of Claim 5.
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.
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.
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.
2. Claims 1, 22, and 25 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 is directed to methods of increasing CAR-T cell persistence in a mammalian subject, the method(s) comprising the step of administering to the subject an effective amount of a CAR-T cell composition and a therapeutically effective amount of an Akt inhibitor to increase the persistence of the CAR-T cells.
The term “therapeutically effective amount” in Claim 1 is a relative term which renders the claim indefinite. The term “therapeutically effective amount” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
The claim(s) denote(s) that there is an amount of the pharmaceutical composition comprising the Akt inhibitor, that, upon administration to the subject, is not, in fact, a “therapeutically effective amount” (syn. sub-therapeutic) to achieve some unrecited physiological effect, nor increase the persistence of the CAR-T cells, thereby increasing CAR-T cell persistence in the mammalian subject.
The phrase “an effective amount” has been held to be indefinite when the claim fails to state the function which is to be achieved and more than one effect can be implied from the specification or the relevant art. In reFredericksen, 213 F.2d 547, 102 USPQ 35 (CCPA 1954). MPEP 2173.05(c)
A claim may be rendered indefinite by reference to an object that is variable. (MPEP §2173.05(b)).
A “therapeutically effective amount” is a functional property that is dependent upon many different variable parameters, including, but not limited to:
the type of human or non-human animal subject to be treated [parameter 1];
the structure(s) of the Akt inhibitor [parameter 2];
the administration route [parameter 3];
the Akt inhibitor dosage(s) administered [parameter 4];
the disease/disorder/condition to be treated [parameter 5];
the phenotypic response to be achieved [parameter 6]; and
the type of supplemental treatments, and corresponding phenotypic response(s) to be achieved [parameter 7].
Parameter 1
The claims are broad for encompassing about 6,400 mammalian species (including humans), distributed in about 1,200 genera, about 152 families and about 29 orders (Mammal, en.wikipedia.org/wiki/Mammal, last visited August 31, 2022; of record).
At best, Example 3 is limited to mouse subjects.
Parameter 2
The claims are directed to the single Akt inhibitor species triciribine.
Parameter 3
The claimed methods are recited at a high level of generality for the multitude of anatomically distinct administration routes (e.g. [0078], “carried out in any convenient manner”), including, but not limited to, delivery and administration systemically, regionally or locally, or by any route, for example, by injection, infusion, orally, alimentary, ingestion, inhalation, mucosal, respiration, intranasal, intubation, intrapulmonary, intrapulmonary instillation, buccal, sublingual, otopically, transdermally, dermal, intradermal, subcutaneously, parenterally, transmucosally, rectally, intracavity, intraglandular, intra-pleurally, intraperitoneally, intravenously, intrarterial, intravascular, intramuscularly, intracranially, intra-spinal, intrathecal, iontophoretic, intraocular, ophthalmic, optical, intraorgan, or intralymphatic (e.g. High et al (U.S. 2015/0111955, [0077]).
Similarly, Perez et al (WO 17/070395; of record in IDS) is considered relevant prior art for having disclosed the Akt inhibitor pharmaceutical may be administered to the subject via an enormous genus of anatomically distinct routes, including, but not limited to, intravenous, intramuscular, subcutaneous, intraperitoneal, spinal or other parenteral routes of administration, for example by injection or infusion, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion, topical, epidermal or mucosal route of administration, for example, intranasally, vaginally, rectally, sublingually or topically (e.g. [0041]).
Applicant prophesizes intraperitoneal injection of an undisclosed triciribine dosage (e.g. Example 3, “be injected i.p. with TCN once a week”).
Parameter 4
The claims are broad for reasonably encompassing an enormous genus of triciribine dosages to be administered to the subject, per the arbitrary and subjective discretion of the attending physician, relative to age, weight, tumor size, extent of infection or metastasis, condition of the subject [0076].
The claims are broad for reasonably encompassing an enormous genus of physiologically and phenotypically different results, which evokes the question: A therapeutically effective amount to do what?
The claim(s) denote(s) that there is an amount of the pharmaceutical composition comprising the Akt inhibitor, that, upon administration to the subject, is not, in fact, a “therapeutically effective amount” (syn. sub-therapeutic) to achieve some unrecited physiological effect, nor increase the persistence of the CAR-T cells, thereby increasing CAR-T cell persistence in the mammalian subject.
The phrase “therapeutically effective amount” renders the claim indefinite because it is unclear to what phenotypic and/or physiological result “therapeutically effective amount” refers.
A claim may be rendered indefinite by reference to an object that is variable. (MPEP §2173.05(b))
Does “therapeutically effective amount” refer back to some presently unrecited phenotypic and/or physiological result achieved by the Akt inhibitor other than the increased CAR-T cell persistence?
Does “therapeutically effective amount” refer back to some presently unrecited phenotypic and/or physiological result achieved per the increased CAR-T cell persistence, that is not achieved by the CAR-T cells in the absence of increased CAR-T cell persistence?
Or, does “therapeutically effective amount” refer to some other, presently unrecited phenotypic and/or physiological result?
Wang et al (Concomitant Targeting of Tumor Cells and Induction of T-cell
Response Synergizes to Effectively Inhibit Trastuzumab-Resistant Breast Cancer, Cancer Research 72(17): 4417-4428, 2012) is considered relevant prior art for having taught a method of treating cancer in a mammalian, to wit, mouse, subject comprising the step of administering triciribine to said subject.
Wang et al taught that Phase I and II clinical trials showed that triciribine's safety and side effects are dose-dependent. Triciribine treatment was not efficacious (syn. not a “therapeutically effective amount”) against advanced breast cancer, colon, and lung cancer, even at very high doses (e.g. pg 4426, col. 2).
Wang et al’s experimental data fail to demonstrate a statistically meaningful therapeutic effect of triciribine alone for reducing tumor volume in the mouse cancer model, let alone increased persistence of T cells.
Wang et al taught that the art recognizes that "over the past years, it has increasingly
been recognized that most cancer drugs developed on the basis of cell culture and xenograft studies have not translated well into the clinic" (e.g pg 4418, col. 1).
Perez et al (WO 17/070395; of record in IDS) is considered relevant prior art for having disclosed the Akt inhibitor pharmaceutical dosage may be as little as 1nM, or as much as 1mM (e.g. [0110]), a range of 6 orders of magnitude.
While Perez et al disclosed examples of culturing T cells in vitro with an Akt inhibitor, Perez et al is silent to administering Akt inhibitors in vivo in combination with CAR-T cells.
While Figures 1-3 disclose in vitro treatment of primary PBMCs and CAR-T cells with triciribine at a concentration of 1uM, 3uM, 10uM, and 30uM, the instant claims are far broader in scope than the four specific concentration species disclosed.
Example 3 is merely prophetic, failing to disclose the actual dosage of triciribine administered to the mouse subject.
Parameter 5
The claims are broad for encompassing an enormous genus of diseases/disorders/conditions to be treated, including, but not limited to, an enormous genus of etiologically and pathologically distinct cancers [0080], including viral-induced cancers.
The claims are broad for reasonably encompassing an enormous genus of etiologically and pathologically distinct diseases/disorders/conditions.
Espe (Malacards: The Human Disease Database, Resource Review, J. Medical Library Association 106(1): 2 pages, doi: dx.doi.org/10.5195/jmla.2018.253, January, 2018; of record) is considered relevant prior art for having taught that there are at least 26,000 recognized genetic diseases afflicting humans (e.g. pg 1, col. 1).
At best, the specification as a whole, and Example 3, is/are directed to the single disease/disorder/condition species of B-cell tumor, per NALM6 tumor cells used to generate the mouse tumor xenograft model.
Parameter 6
The claims are broad for encompassing an enormous genus of phenotypic responses to be achieved. The specification discloses the treatment to include curing, ameliorating, stabilizing, or preventing a disease, condition, or disorder;
improvement of the disease, condition, or disorder;
removal of the cause of the disease, condition, or disorder;
relief of symptoms, rather than curing, the disease, condition, or disorder;
minimizing or partially or completely inhibiting development of the disease, condition, or disorder; or
supportive treatment employed to supplement another specific therapy directed toward the improvement of the disease, condition, or disorder [0039, 41].
The specification does not disclose a definition for “prevents” or “preventing”, and thus is interpreted according to its plain meaning, which is “to keep from happening or existing” (www.merriam-webster.com/dictionary/prevent; last visited March 4, 2025; of record).
Example 3 is merely prophetic, failing to disclose the phenotypic responses of the thus-administered CAR-T cells, e.g. the type and degree of therapeutic effect, and failing to disclose the thus-administered amount of the triciribine actually increased the amount of persistence, if any, of the CAR-T cells in vivo.
Parameter 7
The claims are broad for encompassing an enormous genus of supplemental treatments, including, but not limited to, immunosuppressive agents, radiation treatment, bone marrow transplantation, and chemotherapy [0079].
The recitation implies a genus of unrecited and undisclosed phenotypic results [parameters 5, 6, 7] by which the therapeutically effective dose [parameter 4] is to be determined and/or identified, whereby the therapeutically effective amount of the Akt inhibitor compound triciribine is recited at a high level of generality and administered via the enormous genus of anatomically distinct routes [parameter 3] to the broad genus of about 6400 mammalian species [parameter 1] are each a result-effective variable dependent upon many different parameters, thereby rendering the claim indefinite.
See further discussion below in the 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, rejections.
The instant claims as a whole do not apprise one of ordinary skill in the art of its scope and, therefore, does not serve the notice function required by 35 U.S.C. 112, second paragraph, by providing clear warning to others as to what constitutes infringement of the patent.
Dependent claims are included in the basis of the rejection because they do not correct the primary deficiencies of the independent claims.
Response to Arguments
Applicant argues that amendments to the claim set render the prior rejection moot.
Applicant’s argument(s) has been fully considered, but is not persuasive. The claim(s) denote(s) that there is an amount of the pharmaceutical composition comprising the Akt inhibitor, that, upon administration to the subject, is not, in fact, a “therapeutically effective amount” (syn. sub-therapeutic) to achieve some unrecited physiological effect, nor increase the persistence of the CAR-T cells, thereby increasing CAR-T cell persistence in the mammalian subject.
A claim may be rendered indefinite by reference to an object that is variable. (MPEP §2173.05(b))
Applicant fails to clarify on the record what does/does not objectively fulfill a “therapeutically effective amount” of the triciribine, as opposed to a non- or sub-therapeutically effective amount, nor what phenotypic and/or physiological result is to be achieved by the “therapeutically effective amount” of the triciribine.
When functional claim language is found indefinite, it typically lacks an adequate written description under §112(a), because an indefinite, unbounded functional limitation would cover a plurality of undisclosed structures and/or method steps of performing a function and indicate that the inventor has not provided sufficient disclosure to show possession of the invention. Thus, in most cases, a §112(b) rejection that is based on functional language having unclear (or no) claim boundaries should be accompanied by a rejection under §112(a) based on failure to provide a written description for the claim. See MPEP 2173.05(g).
3. Claims 1, 22, and 25 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.
Claim 1 is directed to methods of increasing CAR-T cell persistence in a mammalian subject, the method(s) comprising the step of administering to the subject an effective amount of a CAR-T cell composition and a therapeutically effective amount of an Akt inhibitor to increase the persistence of the CAR-T cells.
The claim(s) denote(s) that there is an amount of the pharmaceutical composition comprising the Akt inhibitor, that, upon administration to the subject, is not, in fact, a “therapeutically effective amount” (syn. sub-therapeutic) to achieve some unrecited physiological effect, nor increase the persistence of the CAR-T cells, thereby increasing CAR-T cell persistence in the mammalian subject.
The Examiner incorporates herein the above 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, rejection.
In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described by their complete structure. To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. The disclosure of a single species is rarely, if ever, sufficient to describe a broad genus, particularly when the specification fails to describe the features of that genus, even in passing. (see In re Shokal 113USPQ283(CCPA1957); Purdue Pharma L.P. vs Faulding Inc. 56 USPQ2nd 1481 (CAFC 2000).
The court explained that “reading a claim in light of the specification, to thereby interpret limitations explicitly recited in the claim, is a quite different thing from ‘reading limitations of the specification into a claim,’ to thereby narrow the scope of the claim by implicitly adding disclosed limitations which have no express basis in the claim.” The court found that applicant was advocating the latter, i.e., the impermissible importation of subject matter from the specification into the claim.). See also In re Morris, 127 F.3d 1048, 1054-55, 44 USPQ2d 1023, 1027-28 (Fed. Cir. 1997).
United States Court of Appeals for the Federal Circuit, Regents of the University of Minnesota v. Gilead Sciences, Inc (Case 21-2168; decided March 6, 2023).
Written description of a broad genus requires description not only of the outer limits of the genus but also of either a representative number of members of the genus or structural features common to the members of the genus, in either case with enough precision that a relevant artisan can visualize or recognize the members of the genus. See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1350−52 (Fed. Cir. 2010) (en banc). A broad outline of a genus’s perimeter is insufficient. See id.
It is understood that in order to meaningfully treat the subject, and thereby satisfy the requirements of 35 U.S.C. 101 (See MPEP 2107.01 III, Therapeutic or Pharmacological Utility), a therapeutically effective amount or dose of the RNAs expressing the CLDN6, p53, and PRAME polypeptides must be administered to the subject, thereby achieving some real-world, clinically meaningful effect, and thereby being of “immediate benefit to the public”.
The phrase “an effective amount” has been held to be indefinite when the claim fails to state the function which is to be achieved and more than one effect can be implied from the specification or the relevant art. In reFredericksen, 213 F.2d 547, 102 USPQ 35 (CCPA 1954). MPEP 2173.05(c)
A claim may be rendered indefinite by reference to an object that is variable. (MPEP §2173.05(b)).
A “therapeutically effective amount” is a functional property that is dependent upon many different variable parameters, including, but not limited to:
the type of human or non-human animal subject to be treated [parameter 1];
the structure(s) of the Akt inhibitor [parameter 2];
the administration route [parameter 3];
the Akt inhibitor dosage(s) administered [parameter 4];
the disease/disorder/condition to be treated [parameter 5];
the phenotypic response to be achieved [parameter 6]; and
the type of supplemental treatments, and corresponding phenotypic response(s) to be achieved [parameter 7].
Parameter 1
The claims are broad for encompassing about 6,400 mammalian species (including humans), distributed in about 1,200 genera, about 152 families and about 29 orders (Mammal, en.wikipedia.org/wiki/Mammal, last visited August 31, 2022; of record).
At best, Example 3 is limited to mouse subjects.
Parameter 2
The claims are directed to the single Akt inhibitor species triciribine.
Parameter 3
The claimed methods are recited at a high level of generality for the multitude of anatomically distinct administration routes (e.g. [0078], “carried out in any convenient manner”), including, but not limited to, delivery and administration systemically, regionally or locally, or by any route, for example, by injection, infusion, orally, alimentary, ingestion, inhalation, mucosal, respiration, intranasal, intubation, intrapulmonary, intrapulmonary instillation, buccal, sublingual, otopically, transdermally, dermal, intradermal, subcutaneously, parenterally, transmucosally, rectally, intracavity, intraglandular, intra-pleurally, intraperitoneally, intravenously, intrarterial, intravascular, intramuscularly, intracranially, intra-spinal, intrathecal, iontophoretic, intraocular, ophthalmic, optical, intraorgan, or intralymphatic (e.g. High et al (U.S. 2015/0111955, [0077]).
Similarly, Perez et al (WO 17/070395; of record in IDS) is considered relevant prior art for having disclosed the Akt inhibitor pharmaceutical may be administered to the subject via an enormous genus of anatomically distinct routes, including, but not limited to, intravenous, intramuscular, subcutaneous, intraperitoneal, spinal or other parenteral routes of administration, for example by injection or infusion, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion, topical, epidermal or mucosal route of administration, for example, intranasally, vaginally, rectally, sublingually or topically (e.g. [0041]).
Applicant prophesizes intraperitoneal injection of an undisclosed triciribine dosage (e.g. Example 3, “be injected i.p. with TCN once a week”).
Parameter 4
The claims are broad for reasonably encompassing an enormous genus of triciribine dosages to be administered to the subject, per the arbitrary and subjective discretion of the attending physician, relative to age, weight, tumor size, extent of infection or metastasis, condition of the subject [0076].
The claims are broad for reasonably encompassing an enormous genus of physiologically and phenotypically different results, which evokes the question: A therapeutically effective amount to do what?
The claim(s) denote(s) that there is an amount of the pharmaceutical composition comprising the Akt inhibitor, that, upon administration to the subject, is not, in fact, a “therapeutically effective amount” (syn. sub-therapeutic) to achieve some unrecited physiological effect, nor increase the persistence of the CAR-T cells, thereby increasing CAR-T cell persistence in the mammalian subject.
The phrase “therapeutically effective amount” renders the claim indefinite because it is unclear to what phenotypic and/or physiological result “therapeutically effective amount” refers.
A claim may be rendered indefinite by reference to an object that is variable. (MPEP §2173.05(b))
Does “therapeutically effective amount” refer back to some presently unrecited phenotypic and/or physiological result achieved by the Akt inhibitor other than the increased CAR-T cell persistence?
Does “therapeutically effective amount” refer back to some presently unrecited phenotypic and/or physiological result achieved per the increased CAR-T cell persistence, that is not achieved by the CAR-T cells in the absence of increased CAR-T cell persistence?
Or, does “therapeutically effective amount” refer to some other, presently unrecited phenotypic and/or physiological result?
Wang et al (Concomitant Targeting of Tumor Cells and Induction of T-cell
Response Synergizes to Effectively Inhibit Trastuzumab-Resistant Breast Cancer, Cancer Research 72(17): 4417-4428, 2012) is considered relevant prior art for having taught a method of treating cancer in a mammalian, to wit, mouse, subject comprising the step of administering triciribine to said subject.
Wang et al taught that Phase I and II clinical trials showed that triciribine's safety and side effects are dose-dependent. Triciribine treatment was not efficacious (syn. not a “therapeutically effective amount”) against advanced breast cancer, colon, and lung cancer, even at very high doses (e.g. pg 4426, col. 2).
Wang et al’s experimental data fail to demonstrate a statistically meaningful therapeutic effect of triciribine alone for reducing tumor volume in the mouse cancer model, let alone increased persistence of T cells.
Wang et al taught that the art recognizes that "over the past years, it has increasingly
been recognized that most cancer drugs developed on the basis of cell culture and xenograft studies have not translated well into the clinic" (e.g pg 4418, col. 1).
Perez et al (WO 17/070395; of record in IDS) is considered relevant prior art for having disclosed the Akt inhibitor pharmaceutical dosage may be as little as 1nM, or as much as 1mM (e.g. [0110]), a range of 6 orders of magnitude.
While Perez et al disclosed examples of culturing T cells in vitro with an Akt inhibitor, Perez et al is silent to administering Akt inhibitors in vivo in combination with CAR-T cells.
While Figures 1-3 disclose in vitro treatment of primary PBMCs and CAR-T cells with triciribine at a concentration of 1uM, 3uM, 10uM, and 30uM, the instant claims are far broader in scope than the four specific concentration species disclosed.
Example 3 is merely prophetic, failing to disclose the actual dosage of triciribine administered to the mouse subject.
Parameter 5
The claims are broad for encompassing an enormous genus of diseases/disorders/conditions to be treated, including, but not limited to, an enormous genus of etiologically and pathologically distinct cancers [0080], including viral-induced cancers.
The claims are broad for reasonably encompassing an enormous genus of etiologically and pathologically distinct diseases/disorders/conditions.
Espe (Malacards: The Human Disease Database, Resource Review, J. Medical Library Association 106(1): 2 pages, doi: dx.doi.org/10.5195/jmla.2018.253, January, 2018; of record) is considered relevant prior art for having taught that there are at least 26,000 recognized genetic diseases afflicting humans (e.g. pg 1, col. 1).
At best, the specification as a whole, and Example 3, is/are directed to the single disease/disorder/condition species of B-cell tumor, per NALM6 tumor cells used to generate the mouse tumor xenograft model.
Parameter 6
The claims are broad for encompassing an enormous genus of phenotypic responses to be achieved. The specification discloses the treatment to include curing, ameliorating, stabilizing, or preventing a disease, condition, or disorder;
improvement of the disease, condition, or disorder;
removal of the cause of the disease, condition, or disorder;
relief of symptoms, rather than curing, the disease, condition, or disorder;
minimizing or partially or completely inhibiting development of the disease, condition, or disorder; or
supportive treatment employed to supplement another specific therapy directed toward the improvement of the disease, condition, or disorder [0039, 41].
The specification does not disclose a definition for “prevents” or “preventing”, and thus is interpreted according to its plain meaning, which is “to keep from happening or existing” (www.merriam-webster.com/dictionary/prevent; last visited March 4, 2025; of record).
Example 3 is merely prophetic, failing to disclose the phenotypic responses of the thus-administered CAR-T cells, e.g. the type and degree of therapeutic effect, and failing to disclose the thus-administered amount of the triciribine actually increased the amount of persistence, if any, of the CAR-T cells in vivo.
Parameter 7
The claims are broad for encompassing an enormous genus of supplemental treatments, including, but not limited to, immunosuppressive agents, radiation treatment, bone marrow transplantation, and chemotherapy [0079].
The claims fail to recite, and the specification fails to disclose, a first triciribine dosage [parameter 4], e.g. 1nM, administered via a first anatomical route [parameter 3], e.g. subcutaneously, to a first mammalian subject [parameter 1], e.g. a canine, that is necessarily and predictably a “therapeutically effective amount” to treat an enormous genus of etiologically and pathologically distinct diseases/disorders/conditions [parameter 5], e.g. lymphoma, more specifically, cure [parameter 6] lymphoma, as opposed to a second triciribine dosage [parameter 4], e.g. 5nM, administered via a second anatomical route [parameter 3], e.g. intramuscularly, to a second mammalian subject [parameter 1], e.g. a mouse, that is necessarily and predictably a “therapeutically effective amount” to treat an enormous genus of etiologically and pathologically distinct diseases/disorders/conditions [parameter 5], e.g. inflammatory bowel disease, more specifically, completely inhibiting the development of [parameter 6] inflammatory bowel disease, for example.
The claims fail to recite, and the specification fails to disclose, how to transform or otherwise modify a first triciribine dosage [parameter 4] administered via a first anatomical route [parameter 3], e.g. intracranially, to a first mammalian subject [parameter 1], e.g. a non-human primate, that is not necessarily and predictably a “therapeutically effective amount” to increase CAR-T cell persistence and/or treat an enormous genus of etiologically and pathologically distinct diseases/disorders/conditions [parameter 5], e.g. glioblastoma, more specifically, cure [parameter 6] glioblastoma, into a second triciribine dosage [parameter 4], administered via a second anatomical route [parameter 3], e.g. intramuscularly, to said first mammalian subject [parameter 1], that is now necessarily and predictably a “therapeutically effective amount” to increase CAR-T cell persistence and/or achieve a real-world, clinically meaningful treatment of an enormous genus of etiologically and pathologically distinct diseases/disorders/conditions [parameter 5], e.g. glioblastoma, more specifically, cure [parameter 6] glioblastoma, for example.
Without a correlation between structure and function, the claim does little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (“definition by function ... does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is’).
At best, the application as a whole, and Example 3, is/are directed to the single Akt inhibitor species triciribine.
The claims fail to recite, and the specification fails to disclose, the necessary structure/function/action-taking step(s) nexus between the combination of each of:
the type of human or non-human animal subject to be treated [parameter 1];
the structure(s) of the Akt inhibitor [parameter 2];
the administration route [parameter 3];
the Akt inhibitor dosage(s) administered [parameter 4];
the disease/disorder/condition to be treated [parameter 5];
the phenotypic response to be achieved [parameter 6]; and
the type of supplemental treatments, and corresponding phenotypic response(s) to be achieved [parameter 7].
At best, Example 3 is merely prophetic:
failing to disclose both the actual dosage of triciribine administered to the (mouse) subject;
failing to disclose type and degree of therapeutic efficacy of the CAR-T cells and/or triciribine; and
failing to disclose that the thus-administered amount of the triciribine actually increased the persistence of the CAR-T cells in vivo.
A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that “only describe[d] one type of structurally similar antibodies” that “are not representative of the full variety or scope of the genus.”).
Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) (“[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.”). “A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when … the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed.” In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004)
The Federal Circuit has explained that a specification cannot always support expansive claim language and satisfy the requirements of 35 U.S.C. 112 “merely by clearly describing one embodiment of the thing claimed.” LizardTech v. Earth Resource Mapping, Inc., 424 F.3d 1336, 1346, 76 USPQ2d 1731, 1733 (Fed. Cir. 2005).
For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are “representative of the full variety or scope of the genus,” or by the establishment of “a reasonable structure-function correlation.” Such correlations may be established “by the inventor as described in the specification,” or they may be “known in the art at the time of the filing date.” See AbbVie, 759 F.3d at 1300-01, 111 USPQ2d 1780, 1790-91 (Fed. Cir. 2014)
Without a correlation between structure and function, the claim does little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (“definition by function ... does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is’).
In Amgen, Inc., v. Sanofi (872 F.3d 1367 (2017)
At 1375, [T]he use of post-priority-date evidence to show that a patent does not disclose a representative number of species of a claimed genus is proper.
At 1377, [W]e questioned the propriety of the "newly characterized antigen" test and concluded that instead of "analogizing the antibody-antigen relationship to a `key in a lock,'" it was more apt to analogize it to a lock and "a ring with a million keys on it." Id. at 1352.
An adequate written description must contain enough information about the actual makeup of the claimed products — "a precise definition, such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other materials," which may be present in "functional" terminology "when the art has established a correlation between structure and function." Ariad, 598 F.3d at 1350. But both in this case and in our previous cases, it has been, at the least, hotly disputed that knowledge of the chemical structure of an antigen gives the required kind of structure-identifying information about the corresponding antibodies. See, e.g., J.A. 1241 (549:5-
16) (Appellants' expert Dr. Eck testifying that knowing "that an antibody binds to a particular amino acid on PCSK9 ... does not tell you anything at all about the structure of the antibody"); J.A. 1314 (836:9-11) (Appellees' expert Dr. Petsko being informed of Dr. Eck's testimony and responding that "[m]y opinion is that [he's] right"); Centocor, 636 F.3d at 1352 (analogizing the antibody-antigen relationship as searching for a key "on a ring with a million keys on it") (internal citations and quotation marks omitted).
In the instant case, knowing that the initial the initial Akt inhibitor triciribine at an in vitro concentration of 10uM ([0113], “is used because it is the highest non-toxic dose for T cells”) reduces CAR-T cell killing and cytokine secretion in vitro does not tell you anything at all about:
the corresponding “therapeutically effective amount” [parameter 4] triciribine dosages, respectively, that may range from 1nM to 1mM, a range of 6 orders of magnitude, administered via an enormous genus of [parameter 3] anatomically distinct routes, so as to necessarily and predictably achieve, a real-world, clinically meaningful phenotypic [parameters 5-7] result(s), including, but not limited to, increasing persistence of CAR-T cells, curing, ameliorating, stabilizing, or preventing a disease, condition, or disorder, improvement of the disease, condition, or disorder, removal of the cause of the disease, condition, or disorder, relief of symptoms, rather than curing, the disease, condition, or disorder, minimizing or partially or completely inhibiting development of the disease, condition, or disorder, or supportive treatment employed to supplement another specific therapy directed toward the improvement of the disease, condition, or disorder, in the enormously vast genus of about 6400 mammalian subjects [parameter 1].
In Amgen, Inc., v. Sanofi (U.S. Supreme Court, No. 21-757 (2023))
“Amgen seeks to monopolize an entire class of things defined by their function”.
“The record reflects that this class of antibodies does not include just the 26 that Amgen has described by their amino acid sequence, but a “vast” number of additional antibodies that it has not.”
“It freely admits that it seeks to claim for itself an entire universe of antibodies.”
In the instant case, the record reflects that Applicant seeks to claim for themselves an entire universe of CAR-T immunotherapeutic methods.
“They leave a scientist forced to engage in painstaking experimentation to see what works. 159 U.S., at 475.
This is not enablement. More nearly, it is “a hunting license”. Brenner v. Manson, 383 U.S. 519, 536 (1966).
“Amgen has failed to enable all that it has claimed, even allowing for a reasonable degree of experimentation”.
While the “roadmap” would produce functional combinations, it would not enable others to make and use the functional combinations; it would instead leave them to “random trial-and-error discovery”.
“Amgen offers persons skilled in the art little more than advice to engage in “trial and error”.
“The more a party claims for itself the more it must enable.”
“Section 112 of the Patent Act reflects Congress’s judg-ment that if an inventor claims a lot, but enables only a lit-tle, the public does not receive its benefit of the bargain. For more than 150 years, this Court has enforced the stat-utory enablement requirement according to its terms. If the Court had not done so in Incandescent Lamp, it might have been writing decisions like Holland Furniture in the dark. Today’s case may involve a new technology, but the legal principle is the same.
Accordingly, this limited information is not deemed sufficient to reasonably convey to one skilled in the art that the applicant is in possession of the nexus between:
the corresponding “therapeutically effective amount” [parameter 4] triciribine dosages, respectively, that may range from 1nM to 1mM, a range of 6 orders of magnitude;
the enormous genus of [parameter 3] anatomically distinct routes;
so as to necessarily and predictably achieve, a real-world, clinically meaningful phenotypic [parameters 5-7] result(s), including, but not limited to, increasing persistence of CAR-T cells, curing, ameliorating, stabilizing, or preventing a disease, condition, or disorder, improvement of the disease, condition, or disorder, removal of the cause of the disease, condition, or disorder, relief of symptoms, rather than curing, the disease, condition, or disorder, minimizing or partially or completely inhibiting development of the disease, condition, or disorder, or supportive treatment employed to supplement another specific therapy directed toward the improvement of the disease, condition, or disorder;
in the enormously vast genus of about 6400 mammalian subjects [parameter 1], at the time the application was filed.
Applicant is essentially requiring the ordinary artisans to discover for themselves that which Applicant fails to disclose.
Thus, for the reasons outlined above, it is concluded that the claims do not meet the requirements for written description under 35 U.S.C. 112, first paragraph.
See further discussion below in the 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, enablement rejection.
MPEP 2163 - 35 U.S.C. 112(a) and the first paragraph of pre-AIA 35 U.S.C. 112 require that the “specification shall contain a written description of the invention ....” This requirement is separate and distinct from the enablement requirement. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010) (en banc)
Dependent claims are included in the basis of the rejection because they do not correct the primary deficiencies of the independent claims.
Response to Arguments
Applicant argues that the amendment limits the Akt inhibitor to triciribine (TCN), and Figures 1-4 and Examples 2-3 describe the effect of TCN on CAR-T cells.
Applicant’s argument(s) has been fully considered, but is not persuasive. Figures 1-4 and Examples 2-3 describe the effect of TCN on CAR-T cells in vitro, but are silent to the effect of TCN on CAR-T cells in vivo.
The claims are broad for reasonably encompassing an enormous genus of physiologically and phenotypically different results, which evokes the question: A therapeutically effective amount to do what?
The claim(s) denote(s) that there is an amount of the pharmaceutical composition comprising the Akt inhibitor, that, upon administration to the subject, is not, in fact, a “therapeutically effective amount” to achieve some unrecited physiological effect, nor increase the persistence of the CAR-T cells (syn. sub-therapeutic), thereby increasing CAR-T cell persistence in the mammalian subject.
Example 3 is merely prophetic, failing to disclose the phenotypic responses of the thus-administered CAR-T cells, e.g. the type and degree of therapeutic effect, and failing to disclose the thus-administered amount of the triciribine actually increased the amount of persistence, if any, of the CAR-T cells in vivo.
4. Claims 1, 22, and 25 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Claim 1 is directed to methods of increasing CAR-T cell persistence in a mammalian subject, the method(s) comprising the step of administering to the subject an effective amount of a CAR-T cell composition and a therapeutically effective amount of an Akt inhibitor to increase the persistence of the CAR-T cells.
The claim(s) denote(s) that there is an amount of the pharmaceutical composition comprising the Akt inhibitor, that, upon administration to the subject, is not, in fact, “an effective amount” to achieve some unrecited physiological effect, nor increase the persistence of the CAR-T cells (syn. sub-therapeutic), thereby increasing CAR-T cell persistence in the mammalian subject.
The Examiner incorporates herein the above 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, and 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, rejections.
While determining whether a specification is enabling, one considers whether the claimed invention provides sufficient guidance to make and use the claimed invention. If not, whether an artisan would have required undue experimentation to make and use the claimed invention and whether working examples have been provided. When determining whether a specification meets the enablement requirements, some of the factors that need to be analyzed are: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, and whether the quantity of any necessary experimentation to make or use the invention based on the content of the disclosure is “undue” (In re Wands, 858 F.2d 731, 737, 8 USPQ2ds 1400, 1404 (Fed. Cir. 1988)). Furthermore, USPTO does not have laboratory facilities to test if an invention will function as claimed when working examples are not disclosed in the specification. Therefore, enablement issues are raised and discussed based on the state of knowledge pertinent to an art at the time of the invention. And thus, skepticism raised in the enablement rejections are those raised in the art by artisans of expertise.
In Amgen, Inc., v. Sanofi (872 F.3d 1367 (2017)
At 1375, [T]he use of post-priority-date evidence to show that a patent does not disclose a representative number of species of a claimed genus is proper.
At 1377, [W]e questioned the propriety of the "newly characterized antigen" test and concluded that instead of "analogizing the antibody-antigen relationship to a `key in a lock,'" it was more apt to analogize it to a lock and "a ring with a million keys on it." Id. at 1352.
An adequate written description must contain enough information about the actual makeup of the claimed products — "a precise definition, such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other materials," which may be present in "functional" terminology "when the art has established a correlation between structure and function." Ariad, 598 F.3d at 1350. But both in this case and in our previous cases, it has been, at the least, hotly disputed that knowledge of the chemical structure of an antigen gives the required kind of structure-identifying information about the corresponding antibodies. See, e.g., J.A. 1241 (549:5-
16) (Appellants' expert Dr. Eck testifying that knowing "that an antibody binds to a particular amino acid on PCSK9 ... does not tell you anything at all about the structure of the antibody"); J.A. 1314 (836:9-11) (Appellees' expert Dr. Petsko being informed of Dr. Eck's testimony and responding that "[m]y opinion is that [he's] right"); Centocor, 636 F.3d at 1352 (analogizing the antibody-antigen relationship as searching for a key "on a ring with a million keys on it") (internal citations and quotation marks omitted).
In the instant case, knowing that the initial the initial Akt inhibitor triciribine at an in vitro concentration of 10uM ([0113], “is used because it is the highest non-toxic dose for T cells”) reduces CAR-T cell killing and cytokine secretion in vitro does not tell you anything at all about:
the corresponding “therapeutically effective amount” [parameter 4] triciribine dosages, respectively, that may range from 1nM to 1mM, a range of 6 orders of magnitude, administered via an enormous genus of [parameter 3] anatomically distinct routes, so as to necessarily and predictably achieve, a real-world, clinically meaningful phenotypic [parameters 5-7] result(s), including, but not limited to, increasing persistence of CAR-T cells, curing, ameliorating, stabilizing, or preventing a disease, condition, or disorder, improvement of the disease, condition, or disorder, removal of the cause of the disease, condition, or disorder, relief of symptoms, rather than curing, the disease, condition, or disorder, minimizing or partially or completely inhibiting development of the disease, condition, or disorder, or supportive treatment employed to supplement another specific therapy directed toward the improvement of the disease, condition, or disorder, in the enormously vast genus of about 6400 mammalian subjects [parameter 1].
In Amgen, Inc., v. Sanofi (U.S. Supreme Court, No. 21-757 (2023))
“Amgen seeks to monopolize an entire class of things defined by their function”.
“The record reflects that this class of antibodies does not include just the 26 that Amgen has described by their amino acid sequence, but a “vast” number of additional antibodies that it has not.”
“It freely admits that it seeks to claim for itself an entire universe of antibodies.”
In the instant case, the record reflects that Applicant seeks to claim for themselves an entire universe of CAR-T immunotherapeutic methods.
“They leave a scientist forced to engage in painstaking experimentation to see what works. 159 U.S., at 475.
This is not enablement. More nearly, it is “a hunting license”. Brenner v. Manson, 383 U.S. 519, 536 (1966).
“Amgen has failed to enable all that it has claimed, even allowing for a reasonable degree of experimentation”.
While the “roadmap” would produce functional combinations, it would not enable others to make and use the functional combinations; it would instead leave them to “random trial-and-error discovery”.
“Amgen offers persons skilled in the art little more than advice to engage in “trial and error”.
“The more a party claims for itself the more it must enable.”
“Section 112 of the Patent Act reflects Congress’s judg-ment that if an inventor claims a lot, but enables only a lit-tle, the public does not receive its benefit of the bargain. For more than 150 years, this Court has enforced the stat-utory enablement requirement according to its terms. If the Court had not done so in Incandescent Lamp, it might have been writing decisions like Holland Furniture in the dark. Today’s case may involve a new technology, but the legal principle is the same.
Accordingly, this limited information is not deemed sufficient to reasonably convey to one skilled in the art that the applicant is in possession of the nexus between:
the corresponding “therapeutically effective amount” [parameter 4] triciribine dosages, respectively, that may range from 1nM to 1mM, a range of 6 orders of magnitude;
the enormous genus of [parameter 3] anatomically distinct routes;
so as to necessarily and predictably achieve, a real-world, clinically meaningful phenotypic [parameters 5-7] result(s), including, but not limited to, increasing persistence of CAR-T cells, curing, ameliorating, stabilizing, or preventing a disease, condition, or disorder, improvement of the disease, condition, or disorder, removal of the cause of the disease, condition, or disorder, relief of symptoms, rather than curing, the disease, condition, or disorder, minimizing or partially or completely inhibiting development of the disease, condition, or disorder, or supportive treatment employed to supplement another specific therapy directed toward the improvement of the disease, condition, or disorder;
in the enormously vast genus of about 6400 mammalian subjects [parameter 1], at the time the application was filed.
Applicant is essentially requiring the ordinary artisans to discover for themselves that which Applicant fails to disclose.
Reliance on animal models is not predictive of clinical outcome. This has been complicated by the inability to extrapolate delivery methods in animals with those in humans or higher animals.
As discussed above, Wang et al (Concomitant Targeting of Tumor Cells and Induction of T-cell Response Synergizes to Effectively Inhibit Trastuzumab-Resistant Breast Cancer, Cancer Research 72(17): 4417-4428, 2012) is considered relevant prior art for having taught a method of treating cancer in a mammalian, to wit, mouse, subject comprising the step of administering triciribine to said subject.
Wang et al taught that Phase I and II clinical trials showed that triciribine's safety and side effects are dose-dependent. Triciribine treatment was not efficacious (syn. not a “therapeutically effective amount”) against advanced breast cancer, colon, and lung cancer, even at very high doses (e.g. pg 4426, col. 2).
Wang et al’s experimental data fail to demonstrate a statistically meaningful therapeutic effect of triciribine alone for reducing tumor volume in the mouse cancer model, let alone increased persistence of T cells.
Wang et al taught that the art recognizes that "over the past years, it has increasingly
been recognized that most cancer drugs developed on the basis of cell culture and xenograft studies have not translated well into the clinic" (e.g pg 4418, col. 1).
Mingozzi and High (Immune responses to AAV vectors: overcoming barriers to successful gene therapy, Blood 122(1): 23-36, 2013) demonstrate that the human findings are not recapitulated from the animal studies (page 26, col 2, “it seemed logical that one could model the human immune response in these animals, but multiple attempts to do so have also failed”). Hence, lessons learned from small animals such as the mice studies could not recapitulate the ability to deliver adequately in humans.
Ferdowsian et al (Primates in Medical Research: A Matter of Convenience, not Sound Science, The Hastings Center, www.thehastingscenter.org/primates-in-medical-research-convenience-not-sound-science/; July 8, 2022; last visited September 27, 2024) is considered relevant art for having taught that, “Today, unlike in the 17th century, scientists easily recognize the truth in the saying “mice lie and monkeys exaggerate,” which points to a well-known problem in biomedical research: using nonhuman primates and other animals in research fails more often than it succeeds.”
The instant portion of the invention, as claimed, falls under the "germ of an idea" concept defined by the CAFC. The court has stated that "patent protection is granted in return for an enabling disclosure, not for vague intimations of general ideas that may or may not be workable". The court continues to say that "tossing out the mere germ of an idea does not constitute an enabling disclosure" and that "the specification, not knowledge in the art, that must supply the novel aspects of an invention in order to constitute adequate enablement". (See Genentech Inc v. Novo Nordisk A/S 42 USPQ2d 1001, at 1005). The claimed methods of using the enormously vast genus of structurally and functionally undisclosed CAR-T cells recited at a high level of generality in combination with the enormously vast genus of structurally and functionally undisclosed Akt inhibitors recited at a high level of generality to necessarily and predictably sufficiently treat an enormous plurality of etiologically and pathologically distinct diseases/disorders/conditions in the enormously vast genus of vertebrate subjects, constitutes such a "germ of an idea".
The courts have stated that reasonable correlation must exist between scope of exclusive right to patent application and scope of enablement set forth in patent application. 27 USPQ2d 1662 Exparte Maizel. In the instant case, in view of the lack of guidance, working examples, breadth of the claims, the level of skill in the art and state of the art at the time of the claimed invention was made, it would have required undue experimentation to make and/or use the invention as claimed.
If little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as to how to make and use the invention in order to be enabling. See, e.g., Chiron Corp. v. Genentech Inc., 363 F.3d 1247, 1254, 70 USPQ2d 1321, 1326 (Fed. Cir. 2004) ("Nascent technology, however, must be enabled with a 'specific and useful teaching.' The law requires an enabling disclosure for nascent technology because a person of ordinary skill in the art has little or no knowledge independent from the patentee's instruction. Thus, the public's end of the bargain struck by the patent system is a full enabling disclosure of the claimed technology." (citations omitted)).
As In re Gardner, Roe and Willey, 427 F.2d 786,789 (C.C.P.A. 1970), the skilled artisan might eventually find out how to use the invention after “a great deal of work”. In the case of In re Gardner, Roe and Willey, the invention was a compound which the inventor claimed to have antidepressant activity, but was not enabled because the inventor failed to disclose how to use the invention based on insufficient disclosure of effective drug dosage. The court held that “the law requires that the disclosure in the application shall inform them how to use, not how to find out how to use for themselves”.
Perrin (Make mouse studies work, Nature (507): 423-425, 2014) taught that the series of clinical trials for a potential therapy can cost hundreds of millions of dollars. The human costs are even greater (pg 423, col. 1). For example, while 12 clinical trials were tested for the treatment of ALS, all but one failed in the clinic (pg 423, col. 2). Experiments necessary in preclinical animal models to characterize new drugs or therapeutic compounds are expensive, time-consuming, and will not, in themselves, lead to new treatments. But without this upfront investment, financial resources for clinical trials are being wasted and [human] lives are being lost (pg 424, col. 1). Animal models are highly variable, and require a large number of animals per test group. Before assessing a drug’s efficacy, researchers should investigate what dose animals can tolerate, whether the drug reaches the relevant tissue at the required dose and how quickly the drug is metabolized or degraded by the body. We estimate that it takes about $30,000 and 6–9 months to characterize the toxicity of a molecule and assess whether enough reaches the relevant tissue and has a sufficient half-life at the target to be potentially effective. If those results are promising, then experiments to test whether a drug can extend an animal’s survival are warranted — this will cost about $100,000 per dose and take around 12 months. At least three doses of the molecule should be tested; this will help to establish that any drug responses are real and suggest what a reasonable dosing level might be. Thus, even assuming the model has been adequately characterized, an investment of $330,000 is necessary just to determine whether a single drug has reasonable potential to treat disease in humans. It could take thousands of patients, several years and hundreds of millions of dollars to move a drug through the clinical development process. The investment required in time and funds is far beyond what any one lab should be expected to do. (pg 425, col.s 2-3). The human costs are even greater: patients with progressive terminal illnesses may have just one shot at an unproven but promising treatment. Clinical trials typically require patients to commit to year or more of treatment, during which they are precluded from pursuing other experimental options (pg 423, col.2 1-3).
Greenberg (Gene Therapy for heart failure, Trends in Cardiovascular Medicine 27: 216-222, 2017) is considered relevant prior art for taught that despite success in experimental animal models, translating gene transfer strategies from the laboratory to the clinic remains at an early stage (Abstract). The success of gene therapy depends on a variety of factors that will ultimately determine the level of transgene expression within the targeted cells. These factors include the vector used for delivery, the method and conditions of delivery of the vector to the [target tissue], the dose that is given and interactions between the host and the vector that alter the efficiency of transfection of [target] cells (e.g. pg 217, col. 1). Failure of therapeutic results may arise because the vector DNA levels were at the lower end of the threshold for dose-response curves in pharmacology studies, and/or only a small proportion of target cells were expressing the therapeutic transgene (e.g. pg 220, col. 1). Although the use of AAVs for gene therapy is appealing, additional information about the best strain of AAVs to use in human patients is needed. Experience indicates that there is a need to carefully consider the dose of the gene therapy vector; however, this has proved to be difficult in early phase developmental studies due to the complexity and cost of such studies (e.g. pg 221, col. 1).
Maguire et al (Viral vectors for gene delivery to the inner ear, Hearing Research 394: e107927, 13 pages, doi.org/10.1016/j.heares.2020.107927, 2020) is considered relevant post-filing art for taught that despite the progress with AAV vectors in the inner ear, little is known regarding the mechanism of transduction of specific cells by AAV within the cochlea (e.g. pg 2, col. 2). There are limitations to what experiments in mice can tell us about the true translation potential of a new therapeutic (e.g. pg 8, col. 2), e.g. species-related physiological differences between mice and humans (e.g. pg 9, col. 1). The AAV dosage is a significant factor in achieving transduction of the target cell, as insufficient dosage may achieve no transduction of the target cells (e.g. pg 9, col. 2).
Tobias (Mouse Study Used in Research, Multiple Sclerosis News Today, multiplesclerosisnewstoday.com/news-posts/2023/09/08/lets-not-get-overexcited-about-any-mice-study-used-research/; September 8, 2023; last visited September 27, 2024) s considered relevant art for having taught that, “Mice exaggerate and monkeys lie, some researchers jokingly say. (Or is it the other way around?)” The odds of an experimental treatment making it from mouse or monkey to human are very low. Less than 8% of cancer treatments make it from animal studies into a clinical setting, where they’re tested on people, and only 10% of the medications in those clinical trials make it through to government approval. No wonder some researchers joke about mice and monkeys lying and exaggerating.
The claims and specification fail to make up for the deficiencies of the global scientific community.
Applicant is essentially requiring the ordinary artisans to discover for themselves that which Applicant fails to disclose.
Thus, for the reasons outlined above, it is concluded that the claims do not meet the requirements for written description under 35 U.S.C. 112, first paragraph.
MPEP 2163 - 35 U.S.C. 112(a) and the first paragraph of pre-AIA 35 U.S.C. 112 require that the “specification shall contain a written description of the invention ....” This requirement is separate and distinct from the enablement requirement. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010) (en banc)
Dependent claims are included in the basis of the rejection because they do not correct the primary deficiencies of the independent claims.
Response to Arguments
Applicant argues that the claims are enabled.
Applicant’s argument(s) has been fully considered, but is not persuasive. The claims fail to recite, and the specification fails to disclose, the nexus between:
the corresponding “therapeutically effective amount” [parameter 4] triciribine dosages, respectively, that may range from 1nM to 1mM, a range of 6 orders of magnitude;
the enormous genus of [parameter 3] anatomically distinct routes;
so as to necessarily and predictably achieve, a real-world, clinically meaningful phenotypic [parameters 5-7] result(s), including, but not limited to, increasing persistence of CAR-T cells, curing, ameliorating, stabilizing, or preventing a disease, condition, or disorder, improvement of the disease, condition, or disorder, removal of the cause of the disease, condition, or disorder, relief of symptoms, rather than curing, the disease, condition, or disorder, minimizing or partially or completely inhibiting development of the disease, condition, or disorder, or supportive treatment employed to supplement another specific therapy directed toward the improvement of the disease, condition, or disorder;
in the enormously vast genus of about 6400 mammalian subjects [parameter 1].
Example 3 is merely prophetic, failing to disclose the phenotypic responses of the thus-administered CAR-T cells, e.g. the type and degree of therapeutic effect, and failing to disclose the thus-administered amount of the triciribine actually increased the amount of persistence, if any, of the CAR-T cells in vivo.
The claims and specification fail to make up for the deficiencies of the global scientific community.
Applicant is essentially requiring the ordinary artisans to discover for themselves that which Applicant fails to disclose.
Those of ordinary skill in the art have long-recognized that reliance on animal models is not predictive of clinical outcome, and that developing the animal models and/or human clinical trials to discover for themselves that which Applicant fails to disclose is undue experimentation. See discussions in the above rejection.
5. Claim 25 stands 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 22 recites wherein the subject has a cancer. Claim 25 fails to further limit the cancer because those of ordinary skill in the art immediately recognize that it is natural law of cell biology that cancer, by definition, is a TAA-expressing cell undergoing unregulated growth, invasion, or metastasis. Instant specification fails to disclose a TAA-expressing cancer cell that does not undergo unregulated growth, invasion, and/or metastasis in a subject.
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.
Response to Arguments
Applicant argues that amendments to the claim set render the prior rejection moot.
Applicant’s argument(s) has been fully considered, but is not persuasive. Mere amendment to claim dependency fails to overcome the rejection, as both Claims 22 and 25 were discussed in the prior Office Action. Applicant fails to address the substantive issue(s) of the rejection, to wit, the natural law of cell biology that cancer, by definition, is a TAA-expressing cell undergoing unregulated growth, invasion, or metastasis. Instant specification fails to disclose a TAA-expressing cancer cell that does not undergo unregulated growth, invasion, and/or metastasis in a subject.
Conclusion
6. No claims are allowed.
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KEVIN K. HILL
Examiner
Art Unit 1638
/KEVIN K HILL/Primary Examiner, Art Unit 1638
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