Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Detailed Action
This action is in response to the papers filed November 18, 2025.
Amendments
Applicant's response and amendments, filed November 18, 2025, is acknowledged. Applicant has cancelled Claims 3-4, 7-8, amended Claims 1 and 5, withdrawn Claims 9-19, and added new claims, Claims 20-25.
Claims 1-2, 5-6, and 8-25 are pending.
Election/Restrictions
Applicant has elected without traverse the invention of Group II, Claim(s) 1-8, drawn to a method for treating a subject, the method comprising the step(s) of:
(a) adoptively transferring to the subject an effective amount of a composition comprising a CAR-T cell, and
(b) administering to the subject an Akt inhibitor in an amount effective to increase the persistence of the CAR-T cells.
Within Group II, Applicant has elected without traverse the following species, wherein:
i) the alternative CD38 inhibitor species is Triciribine (TCN), as recited in Claims 2 and 6,;
ii) the alternative CAR structural embodiment species is 41BB co-stimulatory domain; and
iii) the alternative immune effector cell species is a cytotoxic T lymphocyte, as recited in Claims 4 and 8.
Claims 1-2, 5-6, and 8-25 are pending.
Claims 9-19 are pending but withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention, there being no allowable generic or linking claim.
Newly submitted Claims 20-21 are directed to an invention that is independent or distinct from the invention originally claimed for the following reasons: the claims are directed to a different Akt inhibitor species.
Since applicant has received an action on the merits for the originally presented invention, this invention has been constructively elected by original presentation for prosecution on the merits. Accordingly, Claims 20-21 are withdrawn from consideration as being directed to a non-elected invention. See 37 CFR 1.142(b) and MPEP § 821.03.
To preserve a right to petition, the reply to this action must distinctly and specifically point out supposed errors in the restriction requirement. Otherwise, the election shall be treated as a final election without traverse. Traversal must be timely. Failure to timely traverse the requirement will result in the loss of right to petition under 37 CFR 1.144. If claims are subsequently added, applicant must indicate which of the subsequently added claims are readable upon the elected invention.
Should applicant traverse on the ground that the inventions are not patentably distinct, applicant should submit evidence or identify such evidence now of record showing the inventions to be obvious variants or clearly admit on the record that this is the case. In either instance, if the examiner finds one of the inventions unpatentable over the prior art, the evidence or admission may be used in a rejection under 35 U.S.C. 103 or pre-AIA 35 U.S.C. 103(a) of the other invention.
Claims 1-2, 5-6, and 22-25 are 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.
Claim Objections
1. Claims 1 and 5 are objected to because of the following informalities:
Where a claim sets forth a plurality of elements or steps, each element or step of the claim should be separated by a line indentation, 37 CFR 1.75(i). See MPEP §608.01(m).
The multiple ‘wherein’ clauses should be separated by line indentation.
Appropriate correction is required.
2. Claim 1 is objected to because of the following informalities: the term “CAR T cell” lacks a hyphen.
Appropriate correction is required. See, for example, Claim 1, line 4 and/or Claim 5, line 1.
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.
3. The prior rejection of Claims 1-4 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of Applicant’s amendment to the claim to recite a method of increasing CAR T cell persistence in a mammalian subject, which the Examiner finds persuasive.
4. Claims 5-6 and 23-25 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 5 is directed to methods of treating a subject, the method(s) comprising the step of administering to the subject an effective amount of a CAR-T cell composition and an 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 CAR-T cells, that, upon administration to the subject, is not, in fact, a therapeutically “effective amount”.
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 increase the persistence of the CAR-T cells, thereby enhancing CAR-T cell therapy in the 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 of the chimeric antigen receptor (CAR) expressed by the T cell [parameter 2];
the CAR-T cell dosage administered [parameter 3];
the structure(s) of the Akt inhibitors [parameter 4];
the Akt inhibitor dosage(s) administered [parameter 5];
the disease/disorder/condition to be treated [parameter 6];
the phenotypic response to be achieved [parameter 7]; and
the type of supplemental treatments, and corresponding phenotypic response(s) to be achieved [parameter 8].
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).
At best, Example 3 is limited to mouse subjects.
Parameter 2
The claims are broad for reasonably encompassing an enormous genus of structurally and functionally different chimeric antigen receptors (CARs) expressed by the T cell, e.g. TRUCK, armored CAR, self-destruct CAR, conditional CAR, tandem CAR, etc.. [0052-58],
wherein said CARs may comprise an enormously vast genus of structurally and functionally different antigen binding domains or fragments thereof [0012], being as little as 5 amino acids [0032], directed to an enormously vast genus of structurally and functionally undisclosed target antigens, and having an enormously broad genus of binding affinities ranging from 10^5/M to 10^11/M [0036] to said enormously vast genus of structurally and functionally undisclosed target antigens, and
wherein said CARs may comprise an enormous genus of structurally and functionally different cytoplasmic signaling sequences and costimulatory sequences, individually and/or in combination and/or subcombinations thereof [0061-64].
Example 3 is merely prophetic, failing to disclose the actual chimeric antigen receptor structure proposed to be administered to the mouse subject.
Parameter 3
The claims are broad for reasonably encompassing an enormous genus of functionally different CAR-T cell populations, as disclosed in [0044-48, 105], and 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, including, but not limited to, 10^4 cells/kg to 10^9 cells/kg body weight [0076].
Example 3 is merely prophetic, failing to disclose the actual number of CAR-T cells proposed to be administered to the mouse subject.
Parameter 4
The claims are broad for reasonably encompassing an enormous genus of structurally different Akt inhibitor compounds, e.g. [0004-7].
At best, the application as a whole, and Example 3, is/are directed to the single Akt inhibitor species triciribine.
Parameter 5
The claims are broad for reasonably encompassing an enormous genus of Akt inhibitor 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].
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 6
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.
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 7
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)
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 8
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 by which the therapeutically effective dose is to be determined and/or identified, whereby the therapeutically effective amount of the enormously vast genus of structurally and functionally undisclosed CAR-T cell dosages and the enormous genus of structurally and functionally undisclosed Akt inhibitor compound dosages administered 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 Claim 5 canceling recitation of “an effective amount” render the prior rejection moot.
Applicant’s argument(s) has been fully considered, but is not persuasive. It is axiomatic that in order to achieve the respective preambles, “increasing CAR T cell persistence” and “enhancing CAR-T cell therapy”, ‘an effective amount’ of the AKT inhibitor must be administered to the subject.
5. Claims 1-2, 5-6, and 22-25 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.
Claims 1 and 5 are directed to methods of treating a subject, the method(s) comprising the step of administering to the subject an effective amount of a CAR-T cell composition and an 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 CAR-T cells, that, upon administration to the subject, is not, in fact, a therapeutically “effective amount”.
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 increase the persistence of the CAR-T cells, thereby enhancing CAR-T cell therapy in the subject.
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 of the chimeric antigen receptor (CAR) expressed by the T cell [parameter 2];
the CAR-T cell dosage administered [parameter 3];
the structure(s) of the Akt inhibitors [parameter 4];
the Akt inhibitor dosage(s) administered [parameter 5];
the disease/disorder/condition to be treated [parameter 6];
the phenotypic response to be achieved [parameter 7]; and
the type of supplemental treatments, and corresponding phenotypic response(s) to be achieved [parameter 8].
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).
At best, Example 3 is limited to mouse subjects.
Parameter 2
The claims are broad for reasonably encompassing an enormous genus of structurally and functionally different chimeric antigen receptors (CARs) expressed by the T cell, e.g. TRUCK, armored CAR, self-destruct CAR, conditional CAR, tandem CAR, etc.. [0052-58],
wherein said CARs may comprise an enormously vast genus of structurally and functionally different antigen binding domains or fragments thereof [0012], being as little as 5 amino acids [0032], directed to an enormously vast genus of structurally and functionally undisclosed target antigens, and having an enormously broad genus of binding affinities, including (Claims 1 and 5 being broader in scope), but not limited to, from 10^5/M to 10^11/M [0036], to said enormously vast genus of structurally and functionally undisclosed target antigens, and
wherein said CARs may comprise an enormous genus of structurally and functionally different cytoplasmic signaling sequences and costimulatory sequences, individually and/or in combination and/or subcombinations thereof [0061-64].
The claims are broad for reasonably encompassing an enormous genus of biologically different viral pathogens.
Virology blog (virology.ws/2013/09/06/how-many-viruses-on-earth/; last visited April 24, 2024) is considered relevant prior art for having taught that there are as many as 320,000 to 100,939,140 virus species.
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) 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).
Thus, the claims are broad for encompassing an enormously vast genus of about 1x10^8 different viral pathogens, and about 26,000 etiologically and pathologically different genetic diseases.
The claims encompass an enormously vast genus of chimeric antigen receptors antigen binding domains composed of an enormously vast genus of structurally and functionally undisclosed antigen-binding domains, or fragments thereof, being as few as 5, 10, 15, 20, 30, 40, 50, 75, 100, 125, 150, 175, 200, 300, 400, or 500, etc… amino acids in length [0032] that are to have the functional properties of:
Recognizing said enormously vast genus of about 1x10^8 different viral pathogens, and about 2.6x10^3 etiologically and pathologically different genetic diseases; and
binding to said enormously vast genus of about 1x10^8 different viral pathogens, and about 2.6x10^3 etiologically and pathologically different genetic diseases with an enormously broad genus of binding affinities [function 2], e.g. ranging from 10^1/M to 10^15/M.
20^5 = 3x10^6 structurally and functionally undisclosed antigen binding domains.
20^50 = 1x10^65 structurally and functionally undisclosed antigen binding domains.
20^100 = 1x10^130 structurally and functionally undisclosed antigen binding domains.
20^200 = 1x10^260 structurally and functionally undisclosed antigen binding domains.
20^300 = an infinite genus of structurally and functionally undisclosed antigen binding domains.
20^400 = an infinite genus of structurally and functionally undisclosed antigen binding domains.
20^500 = an infinite genus of structurally and functionally undisclosed antigen binding domains.
(www.calculator.net/exponent-calculator; last visited May 14, 2025)
Thus, the claims reasonably encompass an infinite and/or enormously vast genus of about 1x10^260, 1x10^130, 1x10^65, and/or 3x10^6 structurally and functionally undisclosed antigen binding domains that are to have the functional properties of:
recognizing [function 1] said enormously vast genus of about 1x10^8 different viral pathogens, and about 2.6x10^3 etiologically and pathologically different genetic diseases; and
binding to [function 2] said enormously vast genus of about 1x10^8 different viral pathogens, and about 2.6x10^3 etiologically and pathologically different genetic diseases with an enormously broad genus of binding affinities, e.g. ranging from 10^1/M to 10^15/M.
Srivastava and Riddell (Engineering CAR-T cells: Design concepts, Trends Immunol. 36(8): 494-502; available online July 15, 2015) is considered relevant prior art for having taught that many challenges remain in improving CAR-T safety and efficacy, as a major challenge is to ensure elimination of target cells, e.g. tumor cells, while sparing healthy tissue and minimizing toxicity (e.g. pg 494, col. 2). The mechanisms underlying TCR sensitivity and concomitant specificity are not fully understood (e.g. pg 498, col. 2).
The type and number of intracellular signaling domains strongly influences the T cell’s ability to differentiate and acquire full effector functions (e.g. Abstract), and remains an unresolved issue (e.g. Table 2), as another mechanism of signal amplification in TCR recognition that is lacking with CARs involves the interaction of coreceptors. Whether the CAR forms a synapse and clusters in a manner similar to TCRs or interacts with endogenous TCR/CD3 complexes and coreceptors remains unresolved (e.g. pg 499, col. 2).
It remains to be determined whether CARs can be designed with avidity thresholds that are sufficiently tuned to distinguish target cells based on high and low levels of target antigen expression. It seems likely that, with such targets, toxicity will be a potentially serious issue (e.g. pg 496, col. 2).
While the biochemical principles of (Kon)/ (Koff) rates, and binding affinity were recognized in the art for being important parameters when designing CARs (Table 2), such values must be determined empirically to optimally activate T cells for tumor recognition (pgs 500-501, joining ¶).
The spatial distance between CARs and their target antigens is important for effective initiation of T cell signaling, but depends on an entirely different set of structural elements related to the location of the epitope on the target molecule and the spacer domain between the CAR antigen binding domain and the T cell membrane. For example, in some studies, the same epitope can activate CAR-T cells with greater efficiency when expressed in a more membrane-proximal position than a membrane-distal position (e.g. pg 498, col. 2).
Example 3 is merely prophetic, failing to disclose the actual chimeric antigen receptor structure proposed to be administered to the mouse subject.
Parameter 3
The claims are broad for reasonably encompassing an enormous genus of functionally different CAR-T cell populations, as disclosed in [0044-48, 105], and 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, including, but not limited to, 10^4 cells/kg to 10^9 cells/kg body weight [0076].
Figueroa et al (Chimeric Antigen Receptor Engineering: A Right Step in the Evolution of Adoptive Cellular Immunotherapy, Int. J. Immunol. 34: 154-187, 2015) is considered relevant prior art for having taught that while CAR immunotherapy shares the common goal of specifically targeting and eradicating target disease cells, the different strategies exploit distinct components of the immune system and their generalized success has been hindered by the paucity of specific antigen targets, resulting in suboptimal responses and unpredictable toxicities (e.g. Abstract).
CARs are designed to comprise intracellular co-stimulatory signaling domains that may promote sequential rounds of T-cell proliferation. T-cell activation and proliferation requires signaling through both the T-cell receptor and co-stimulatory molecules. Once target antigens are recognized, the function and survival of the CAR-T cells depends on the activation of chimeric co-stimulatory receptors (e.g. pg 159). However, some CAR designs demonstrate low proliferative capacity, leading to apoptosis, consequent anergy, and only transient persistence, resulting in limited efficacy against the target cell (e.g. pg 158).
Other factors that contribute to poor efficacy includes the T-cell’s functional characteristics (e.g. pg 158, para 2). Marked differences in phenotypic and differentiation states suggests that distinct populations of T-cells may have specific uses. Characteristics such as suitability for ex vivo expansion, length of engraftment, antigen-dependent proliferative capacity, migratory capability, susceptibility to immunoediting and therapeutic efficacy are critical when defining “optimal” T-cell populations for CAR engineering and clinical use. Nonetheless, selecting defined T-cell subpopulations for ACI engineering purposes adds complexity, difficulty and cost to an already expensive process. an already expensive process. One of the major unresolved issues in the clinical application of CAR-T cell therapy is the optimal number of cells required for a robust antitumor effect. The use of T cells with restricted proliferative capacity will require much higher “cellular doses” than the use of less differentiated T-cells with greater plasticity and replicative capacity, which also affects the degree of engraftment, persistence, replication, self-renewal, differentiation, and anti-target cells activity, as different T-cell types have different intrinsic properties, being more or less efficacious (e.g. pgs 167-168).
Clinical experience has demonstrated suboptimal homing of effector cells to solid tumors, limited engraftment, and generally disappointing results, including adverse events related to on-target/off-tumor effects and no significant clinical response (e.g. pg 170).
The most common systemic toxicity associated with CAR-T cells relates to the systemic inflammatory response, and can result in anaphylaxis, which may be fatal (e.g. pg 172).
Example 3 is merely prophetic, failing to disclose the actual type of T cell subpopulation identity and the number of CAR-T cells proposed to be administered to the mouse subject.
Parameter 4
The claims are broad for reasonably encompassing an enormous genus of structurally different Akt inhibitor compounds, e.g. [0004-7].
Applicant has amended the independent claims to recite a genus of structurally undisclosed purine derivatives that are to have the functional property of inhibiting Akt, be it directly or indirectly.
Perez et al (WO 17/070395; of record in IDS) is considered relevant prior art for having disclosed Akt inhibitor compounds may include small molecules, DNA or RNA polynucleotides, antibodies, peptides, and can either directly act on Akt directly or indirectly (e.g. [0042]), including an enormously vast genus of structurally different compounds (e.g [0106-108]), whereby the Akt inhibitor need only inhibit Akt by as little as 5%, or as much as 100% [0111].
Davis et al (U.S. Patent 6,369,086) is considered relevant prior art for having disclosed an enormously vast (too numerous to count) genus of purine derivatives, e.g. col. 4, line 20-col. 10, line 31; Table 1; col. 28, line 58-col. 38, line 57. While Davis et al contemplate said purine derivatives are to be capable of inhibiting a serine/threonine kinase (e.g. Abstract), Davis et al is silent to said purine derivatives inhibiting Akt directly or indirectly.
Trova et al (U.S. 2002/0091263) is considered relevant prior art for having disclosed an enormously vast (too numerous to count) genus of purine derivatives, e.g. [015-718]. While Trova et al contemplate said purine derivatives are to be capable of inhibiting a serine/threonine kinase (e.g. [0010]), Trovis et al is silent to said purine derivatives inhibiting Akt directly or indirectly. Furthermore, Trovis et al contemplate said purine derivatives have the functional properties of being anti-proliferative agents, which is a different, contradictory function of the instantly claimed invention.
Abbot et al (U.S. 2009/0082332) is considered relevant prior art for having disclosed an enormously vast (too numerous to count) genus of purine derivatives, e.g. [0006-114]. However, Abbot et al contemplate the purine derivatives to act as TLR ligands, thereby inhibiting TLR signaling (e.g. [0004-5], which is a different function of the instantly claimed invention.
Thus, the breadth of the claims reasonably encompasses an essentially infinite and/or enormously vast genus of structurally and functionally undisclosed small molecule compounds that are to have the functional property of inhibiting Akt, either directly or indirectly.
Each small molecule represents its own structural and functional subgenus of compounds, having a different genus of varying structures and binding affinities to varying amino acid targets [function] that may, or may not, inhibit Akt, either directly or indirectly.
The claims fail to recite, and the specification fails to disclose, a first purine derivative [parameter 4] of the infinite and/or enormously vast genus of structurally and functionally undisclosed purine derivatives that does not have the functional property of inhibiting Akt, either directly or indirectly, and it’s corresponding in vivo working dosage [parameter 5], e.g. 1nM, as opposed to a second purine derivative [parameter 4] of the infinite and/or enormously vast genus of structurally and functionally undisclosed purine derivatives that necessarily and predictably has the functional property of inhibiting Akt, either directly or indirectly, and it’s corresponding in vivo working dosage [parameter 5], e.g. 5nM.
The claims fail to recite, and the specification fails to disclose, a first purine derivative [parameter 4] of the infinite and/or enormously vast genus of structurally and functionally undisclosed purine derivatives that, while having the functional property of inhibiting Akt indirectly, does not have the functional property of inhibiting Akt directly, and it’s corresponding in vivo working dosage [parameter 5], e.g. 10nM, as opposed to a second purine derivative [parameter 4] of the infinite and/or enormously vast genus of structurally and functionally undisclosed purine derivatives that necessarily and predictably has the functional property of inhibiting Akt directly, and it’s corresponding in vivo working dosage [parameter 5], e.g. 5nM.
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.
Parameter 5
The claims are broad for reasonably encompassing an enormous genus of Akt inhibitor 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].
Perez et al is considered relevant prior art for having disclosed the 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]).
Perez et al disclosed wherein the Akt inhibitor 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 6
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.
See Parameter 2 discussion above.
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 7
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)
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 8
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, 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 of the chimeric antigen receptor (CAR) expressed by the T cell [parameter 2];
the CAR-T cell dosage administered [parameter 3];
the structure(s) of the Akt inhibitors [parameter 4];
the Akt inhibitor dosage(s) administered [parameter 5];
the disease/disorder/condition to be treated [parameter 6];
the phenotypic response to be achieved [parameter 7]; and
the type of supplemental treatments, and corresponding phenotypic response(s) to be achieved [parameter 8].
The claims fail to recite, and the specification fails to disclose, a first type of T cell [parameter 3], e.g. gamma/delta T cell, it’s corresponding dosage [parameter 3], it’s corresponding CAR antigen-binding domain [parameter 2] of the infinite and/or enormously vast genus of about 1x10^260, 1x10^130, 1x10^65, and/or 3x10^6 structurally and functionally undisclosed antigen binding domains that are to have the functional properties of:
recognizing [function 1] said enormously vast genus of about 1x10^8 different viral pathogens, and about 2.6x10^3 etiologically and pathologically different genetic diseases [parameter 6]; and
binding to [function 2] said enormously vast genus of about 1x10^8 different viral pathogens, and about 2.6x10^3 etiologically and pathologically different genetic diseases [parameter 6] with an enormously broad genus of binding affinities, e.g. ranging from 10^1/M to 10^15/M, and it’s corresponding co-stimulatory and intracellular signaling domains [parameter 2], alone and/or in combination with,
a first Akt inhibitor [parameter 4] of the infinite and/or enormously vast genus of structurally and functionally undisclosed purine derivatives that may inhibit Akt either directly or indirectly, and it’s corresponding dosage [parameter 5], e.g. 1nM, administered via an enormous genus of anatomically distinct routes [parameter 5], e.g. inhalation, so as to necessarily and predictably achieve a real-world, clinically meaningful phenotypic result [parameter 7], e.g. supportive treatment of a supplemental therapy [parameter 8], in the enormously vast genus of about 6400 mammalian subjects [parameter 1], e.g. horse, for example.
The claims fail to recite, and the specification fails to disclose, how to transform or otherwise modify a first type of T cell [parameter 3], e.g. cytotoxic T cell, it’s corresponding dosage [parameter 3], it’s corresponding CAR antigen-binding domain [parameter 2] of the infinite and/or enormously vast genus of about 1x10^260, 1x10^130, 1x10^65, and/or 3x10^6 structurally and functionally undisclosed antigen binding domains that are to have the functional properties of:
recognizing [function 1] said enormously vast genus of about 1x10^8 different viral pathogens, and about 2.6x10^3 etiologically and pathologically different genetic diseases [parameter 6]; and
binding to [function 2] said enormously vast genus of about 1x10^8 different viral pathogens, and about 2.6x10^3 etiologically and pathologically different genetic diseases [parameter 6] with an enormously broad genus of binding affinities, e.g. ranging from 10^1/M to 10^15/M, and it’s corresponding co-stimulatory and intracellular signaling domains [parameter 2], alone and/or in combination with,
a first Akt inhibitor [parameter 4] of the infinite and/or enormously vast genus of about 1x10^130, ^65, ^32, ^30, ^24, ^17, ^13, and/or ^12 structurally undisclosed Akt inhibitors, e.g. small molecules, that may inhibit Akt either directly or indirectly, and it’s corresponding dosage [parameter 5], e.g. 25nM, administered via an enormous genus of anatomically distinct routes [parameter 5], e.g. subcutaneously, that does not necessarily and predictably achieve a real-world, clinically meaningful phenotypic result [parameter 7], e.g. cures cancer, in the enormously vast genus of about 6400 mammalian subjects [parameter 1], e.g. dog, into
a second type of T cell [parameter 3], e.g. Treg cell, it’s corresponding dosage [parameter 3], it’s corresponding CAR antigen-binding domain [parameter 2] of the infinite and/or enormously vast genus of about 1x10^260, 1x10^130, 1x10^65, and/or 3x10^6 structurally and functionally undisclosed antigen binding domains that are to have the functional properties of:
recognizing [function 1] said enormously vast genus of about 1x10^8 different viral pathogens, and about 2.6x10^3 etiologically and pathologically different genetic diseases [parameter 6]; and
binding to [function 2] said enormously vast genus of about 1x10^8 different viral pathogens, and about 2.6x10^3 etiologically and pathologically different genetic diseases [parameter 6] with an enormously broad genus of binding affinities, e.g. ranging from 10^1/M to 10^15/M, and it’s corresponding co-stimulatory and intracellular signaling domains [parameter 2], alone and/or in combination with,
a second Akt inhibitor [parameter 4] of the infinite and/or enormously vast genus of about 1x10^130, ^65, ^32, ^30, ^24, ^17, ^13, and/or ^12 structurally undisclosed Akt inhibitors, e.g. a structurally undisclosed siRNA, that may inhibit Akt either directly or indirectly, and it’s corresponding dosage [parameter 5], e.g. 50nM, administered via an enormous genus of anatomically distinct routes [parameter 5], e.g. intraperitoneally, that now, necessarily and predictably achieves, a real-world, clinically meaningful phenotypic result [parameter 7], e.g. completely inhibiting development of the disease, condition, or disorder, alone and/or in supportive treatment of a supplemental therapy [parameter 8], in the enormously vast genus of about 6400 mammalian subjects [parameter 1], e.g. human, for example.
At best, Example 3 is merely prophetic:
failing to disclose both the actual chimeric antigen receptor structure proposed to be administered to the (mouse) subject;
failing to disclose both the actual number of CAR-T cells proposed to be administered to the (mouse) subject;
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
failing to disclose 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 T cell recited at a high level of generality expresses a chimeric antigen receptor recited at a high level of generality is to have therapeutic properties, and the initial Akt inhibitor recited at high level of generality is to increase the persistence of said initial T cell(s) does not tell you anything at all about:
the enormous genus of functionally distinct T cell populations, each of which are to express an enormous genus of structurally and functionally undisclosed chimeric antigen receptors comprising the infinite and/or enormously vast genus of about 1x10^260, 1x10^130, 1x10^65, and/or 3x10^6 structurally and functionally undisclosed antigen binding domains that are to have the functional properties of:
recognizing [function 1] said enormously vast genus of about 1x10^8 different viral pathogens, and about 2.6x10^3 etiologically and pathologically different genetic diseases [parameter 6]; and
binding to [function 2] said about 1x10^8 different viral pathogens, and about 2.6x10^3 etiologically and pathologically different genetic diseases [parameter 6] with an enormously broad genus of binding affinities, e.g. ranging from 10^1/M to 10^15/M, and it’s corresponding co-stimulatory and intracellular signaling domains [parameter 2],
their corresponding dosage, e.g. ranging from as little as 1x10^3 or as much as 1x10^12 CAR-T cells, to be administered;
alone and/or in combination with,
the infinite and/or enormously vast genus of structurally and functionally undisclosed small molecule compounds that are to have the functional property of inhibiting Akt, either directly or indirectly,
and their corresponding dosages, respectively, that may range from 1nM to 1mM, a range of 6 orders of magnitude, administered via an enormous genus of anatomically distinct routes, so as to necessarily and predictably achieve, a real-world, clinically meaningful phenotypic result, including, but not limited to, 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.
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 enormous genus of functionally distinct T cell populations, each of which are to express an enormous genus of structurally and functionally undisclosed chimeric antigen receptors comprising the infinite and/or enormously vast genus of about 1x10^260, 1x10^130, 1x10^65, and/or 3x10^6 structurally and functionally undisclosed antigen binding domains that are to have the functional properties of:
recognizing [function 1] said enormously vast genus of about 1x10^8 different viral pathogens, and about 2.6x10^3 etiologically and pathologically different genetic diseases [parameter 6]; and
binding to [function 2] said enormously vast genus of about 1x10^8 different viral pathogens, and about 2.6x10^3 etiologically and pathologically different genetic diseases [parameter 6] with an enormously broad genus of binding affinities, e.g. ranging from 10^1/M to 10^15/M, and it’s corresponding co-stimulatory and intracellular signaling domains [parameter 2],
their corresponding dosage, e.g. ranging from as little as 1x10^3 or as much as 1x10^12 CAR-T cells, to be administered;
alone and/or in combination with,
the infinite and/or enormously vast genus of structurally undisclosed Akt inhibitors, e.g. small molecules, that may inhibit Akt either directly or indirectly, and their corresponding dosages that may range from 1nM to 1mM, a range of 6 orders of magnitude, administered via an enormous genus of anatomically distinct routes, so as to necessarily and predictably achieve, a real-world, clinically meaningful phenotypic result, including, but not limited to, 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 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 ordinary artisan would reasonably predict from the instant specification that any CAR-T cell therapy for any mammal will have increased persistence and/or enhanced activity when treated with an Akt inhibitor.
Applicant’s argument(s) has been fully considered, but is not persuasive.
Applicant’s argument is not on point. The limited information provided in the application is not deemed sufficient to reasonably convey to one skilled in the art that the applicant is in possession of the nexus between:
the enormous genus of functionally distinct T cell populations, each of which are to express an enormous genus of structurally and functionally undisclosed chimeric antigen receptors comprising the infinite and/or enormously vast genus of about 1x10^260, 1x10^130, 1x10^65, and/or 3x10^6 structurally and functionally undisclosed antigen binding domains that are to have the functional properties of:
recognizing [function 1] said enormously vast genus of about 1x10^8 different viral pathogens, and about 2.6x10^3 etiologically and pathologically different genetic diseases [parameter 6]; and
binding to [function 2] said enormously vast genus of about 1x10^8 different viral pathogens, and about 2.6x10^3 etiologically and pathologically different genetic diseases [parameter 6] with an enormously broad genus of binding affinities, e.g. ranging from 10^1/M to 10^15/M, and it’s corresponding co-stimulatory and intracellular signaling domains [parameter 2],
their corresponding dosage, e.g. ranging from as little as 1x10^3 or as much as 1x10^12 CAR-T cells, to be administered;
alone and/or in combination with,
the infinite and/or enormously vast genus of structurally undisclosed Akt inhibitors, e.g. small molecules, that may inhibit Akt either directly or indirectly, and their corresponding dosages that may range from 1nM to 1mM, a range of 6 orders of magnitude, administered via an enormous genus of anatomically distinct routes, so as to necessarily and predictably achieve, a real-world, clinically meaningful phenotypic result, including, but not limited to, 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 at the time the application was filed.
Applicant argues that the Akt inhibitor acts directly upon Akt in the CAR-T cells.
Applicant’s argument(s) has been fully considered, but is not persuasive. The claims neither recite nor require the AKT inhibitors to ‘act directly upon Akt’. Rather, as discussed in the rejection, the breadth of the claims encompass the infinite and/or enormously vast genus of structurally undisclosed Akt inhibitors, e.g. small molecules, that may inhibit Akt either directly or indirectly, and their corresponding dosages that may range from 1nM to 1mM, a range of 6 orders of magnitude.
At best, the application as a whole, and Example 3, is/are directed to the single Akt inhibitor species triciribine.
Applicant argues that the method is based on the identification of a previously unknown property of a known purine derivative Akt inhibitor, TCN.
Applicant’s argument(s) has been fully considered, but is not persuasive. The independent claims neither recite nor require the AKT inhibitors to be TCN. Rather, as discussed in the rejection, the breadth of the claims encompass the infinite and/or enormously vast genus of structurally undisclosed Akt inhibitors, e.g. small molecules, that may inhibit Akt either directly or indirectly, and their corresponding dosages that may range from 1nM to 1mM, a range of 6 orders of magnitude.
The limited information provided in the application is not deemed sufficient to reasonably convey to one skilled in the art that the applicant is in possession of the infinite and/or enormously vast genus of structurally undisclosed Akt inhibitors, e.g. small molecules, that may inhibit Akt either directly or indirectly, and their corresponding dosages that may range from 1nM to 1mM, a range of 6 orders of magnitude.
At best, the application as a whole, and Example 3, is/are directed to the single Akt inhibitor species triciribine.
Applicant argues that the structure of the CAR is not germane to the claimed methods.
Applicant’s argument(s) has been fully considered, but is not persuasive. It is axiomatic natural law of cell biology that the structure of the CAR is biologically (syn. functionally) germane to claimed methods of increasing CAR-T cell persistence and/or enhancing CAR-T cell therapy. These cells must have biological immunotherapeutic function, which is directly resulting from the structure of said CARs.
The limited information provided in the application is not deemed sufficient to reasonably convey to one skilled in the art that the applicant is in possession of the nexus between:
the enormous genus of functionally distinct T cell populations, each of which are to express an enormous genus of structurally and functionally undisclosed chimeric antigen receptors comprising the infinite and/or enormously vast genus of about 1x10^260, 1x10^130, 1x10^65, and/or 3x10^6 structurally and functionally undisclosed antigen binding domains that are to have the functional properties of:
recognizing [function 1] said enormously vast genus of about 1x10^8 different viral pathogens, and about 2.6x10^3 etiologically and pathologically different genetic diseases [parameter 6]; and
binding to [function 2] said enormously vast genus of about 1x10^8 different viral pathogens, and about 2.6x10^3 etiologically and pathologically different genetic diseases [parameter 6] with an enormously broad genus of binding affinities, e.g. ranging from 10^1/M to 10^15/M, and it’s corresponding co-stimulatory and intracellular signaling domains [parameter 2],
their corresponding dosage, e.g. ranging from as little as 1x10^3 or as much as 1x10^12 CAR-T cells, to be administered;
alone and/or in combination with,
administered via an enormous genus of anatomically distinct routes, so as to necessarily and predictably achieve, a real-world, clinically meaningful phenotypic result, including, but not limited to, 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 at the time the application was filed.
Applicant argues that the claimed methods are directed to enhancing an existing CAR-T cell therapy, not a new treatment regimen. Therapeutically effective amounts for an existing CAR T cell therapy is known.
Applicant’s argument(s) has been fully considered, but is not persuasive. The claims are broader in scope than “existing CAR-T cell therapy”, reasonably encompassing:
the enormous genus of functionally distinct T cell populations, each of which are to express an enormous genus of structurally and functionally undisclosed chimeric antigen receptors comprising the infinite and/or enormously vast genus of about 1x10^260, 1x10^130, 1x10^65, and/or 3x10^6 structurally and functionally undisclosed antigen binding domains that are to have the functional properties of:
recognizing [function 1] said enormously vast genus of about 1x10^8 different viral pathogens, and about 2.6x10^3 etiologically and pathologically different genetic diseases [parameter 6]; and
binding to [function 2] said enormously vast genus of about 1x10^8 different viral pathogens, and about 2.6x10^3 etiologically and pathologically different genetic diseases [parameter 6] with an enormously broad genus of binding affinities, e.g. ranging from 10^1/M to 10^15/M, and it’s corresponding co-stimulatory and intracellular signaling domains [parameter 2],
their corresponding dosage, e.g. ranging from as little as 1x10^3 or as much as 1x10^12 CAR-T cells, to be administered;
alone and/or in combination with,
administered via an enormous genus of anatomically distinct routes, so as to necessarily and predictably achieve, a real-world, clinically meaningful phenotypic result, including, but not limited to, 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
Applicant argues that amending Claim 1 preamble to recite “increasing CAR T cell persistence” renders the prior rejection moot.
Applicant’s argument(s) has been fully considered, but is not persuasive.
Applicant’s argument is not on point. The limited information provided in the application is not deemed sufficient to reasonably convey to one skilled in the art that the applicant is in possession of the nexus between:
the enormous genus of functionally distinct T cell populations, each of which are to express an enormous genus of structurally and functionally undisclosed chimeric antigen receptors comprising the infinite and/or enormously vast genus of about 1x10^260, 1x10^130, 1x10^65, and/or 3x10^6 structurally and functionally undisclosed antigen binding domains that are to have the functional properties of:
recognizing [function 1] said enormously vast genus of about 1x10^8 different viral pathogens, and about 2.6x10^3 etiologically and pathologically different genetic diseases [parameter 6]; and
binding to [function 2] said enormously vast genus of about 1x10^8 different viral pathogens, and about 2.6x10^3 etiologically and pathologically different genetic diseases [parameter 6] with an enormously broad genus of binding affinities, e.g. ranging from 10^1/M to 10^15/M, and it’s corresponding co-stimulatory and intracellular signaling domains [parameter 2],
their corresponding dosage, e.g. ranging from as little as 1x10^3 or as much as 1x10^12 CAR-T cells, to be administered;
alone and/or in combination with,
the infinite and/or enormously vast genus of structurally undisclosed Akt inhibitors, e.g. small molecules, that may inhibit Akt either directly or indirectly, and their corresponding dosages that may range from 1nM to 1mM, a range of 6 orders of magnitude, administered via an enormous genus of anatomically distinct routes, so as to necessarily and predictably achieve, a real-world, clinically meaningful phenotypic result, including, but not limited to, 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 at the time the application was filed.
Applicant argues that the claims do not recite supplemental treatments, and the specification does not suggest supplemental treatment.
Applicant’s argument(s) has been fully considered, but is not persuasive. The term "comprising" (Claim 1, line 2; Claim 5, line 2) is open-ended and allows for additional, unrecited elements in the claims. MPEP 2111.03 specifically sets forth that the transitional term "comprising", which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. See, e.g., Mars Inc. v. H.J. Heinz Co., 377 F.3d 1369, 1376, 71 USPQ2d 1837, 1843 (Fed. Cir. 2004). Applicant fails to specifically exclude the use of supplemental treatments in either the claims or the specification.
Applicant and/or Applicant’s representative(s) appear to have overlooked that [0079] discloses the CAR-T cell therapies may further comprise the use of chemotherapy, radiation, and/or immunosuppressive agents.
6. Claims 1-2, 5-6, and 22-25 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.
Claims 1 and 5 are directed to methods of treating a subject, the method(s) comprising the step of administering to the subject an effective amount of a CAR-T cell composition and an 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 CAR-T cells, that, upon administration to the subject, is not, in fact, a therapeutically “effective amount”.
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 increase the persistence of the CAR-T cells, thereby enhancing CAR-T cell therapy in the subject.
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.
The Examiner incorporates herein the above 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, written description rejection.
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 T cell recited at a high level of generality expresses a chimeric antigen receptor recited at a high level of generality is to have therapeutic properties, and the initial Akt inhibitor recited at high level of generality is to increase the persistence of said initial T cell(s) does not tell you anything at all about:
the enormous genus of functionally distinct T cell populations, each of which are to express an enormous genus of structurally and functionally undisclosed chimeric antigen receptors comprising the infinite and/or enormously vast genus of about 1x10^260, 1x10^130, 1x10^65, and/or 3x10^6 structurally and functionally undisclosed antigen binding domains that are to have the functional properties of:
recognizing [function 1] said enormously vast genus of about 1x10^8 different viral pathogens, and about 2.6x10^3 etiologically and pathologically different genetic diseases [parameter 6]; and
binding to [function 2] said about 1x10^8 different viral pathogens, and about 2.6x10^3 etiologically and pathologically different genetic diseases [parameter 6] with an enormously broad genus of binding affinities, e.g. ranging from 10^1/M to 10^15/M, and it’s corresponding co-stimulatory and intracellular signaling domains [parameter 2],
their corresponding dosage, e.g. ranging from as little as 1x10^3 or as much as 1x10^12 CAR-T cells, to be administered;
alone and/or in combination with,
the infinite and/or enormously vast genus of structurally and functionally undisclosed small molecule compounds that are to have the functional property of inhibiting Akt, either directly or indirectly,
and their corresponding dosages, respectively, that may range from 1nM to 1mM, a range of 6 orders of magnitude, administered via an enormous genus of anatomically distinct routes, so as to necessarily and predictably achieve, a real-world, clinically meaningful phenotypic result, including, but not limited to, 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.
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 enormous genus of functionally distinct T cell populations, each of which are to express an enormous genus of structurally and functionally undisclosed chimeric antigen receptors comprising the infinite and/or enormously vast genus of about 1x10^260, 1x10^130, 1x10^65, and/or 3x10^6 structurally and functionally undisclosed antigen binding domains that are to have the functional properties of:
recognizing [function 1] said enormously vast genus of about 1x10^8 different viral pathogens, and about 2.6x10^3 etiologically and pathologically different genetic diseases [parameter 6]; and
binding to [function 2] said enormously vast genus of about 1x10^8 different viral pathogens, and about 2.6x10^3 etiologically and pathologically different genetic diseases [parameter 6] with an enormously broad genus of binding affinities, e.g. ranging from 10^1/M to 10^15/M, and it’s corresponding co-stimulatory and intracellular signaling domains [parameter 2],
their corresponding dosage, e.g. ranging from as little as 1x10^3 or as much as 1x10^12 CAR-T cells, to be administered;
alone and/or in combination with,
the infinite and/or enormously vast genus of structurally undisclosed Akt inhibitors, e.g. small molecules, that may inhibit Akt either directly or indirectly, and their corresponding dosages that may range from 1nM to 1mM, a range of 6 orders of magnitude, administered via an enormous genus of anatomically distinct routes, so as to necessarily and predictably achieve, a real-world, clinically meaningful phenotypic result, including, but not limited to, 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 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.
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.
7. Claims 24-25 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.
As a first matter, Claim 25 recites dependency upon Claim 24, and is a duplicate of Claim 24.
As a second matter, Claim 23 recites wherein the subject has a cancer. Claims 24-25 fail 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.
Conclusion
8. No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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KEVIN K. HILL
Examiner
Art Unit 1638
/KEVIN K HILL/Primary Examiner, Art Unit 1638