DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
1. The Election filed July 31, 2026, in response to the Office Action of June 9, 2026, is acknowledged and has been entered. Applicants elected without traverse Group I and the species of a first interchain disulfide bond of cysteine residue substitutions at positions TRAC 84.2 and TRBC 79 and a specific group of second stabilizing mutations from the options in claim 1 of (a), (b), (c), (f), (g), (i), (q), and (r).
Claims 1-2, 4-10, 12-13, 22-26, 28-53, and 56-59 are pending. Claims 22-26, 28-29, 34-45, 47, 49, 51-52, and 56 have been withdrawn from further consideration by the examiner under 35 CFR 1.142(b) as being drawn to non-elected inventions. Claims 1-2, 4-10, 12-13, 30-33, 46, 48, 50, 53, and 57-59 are currently under prosecution as drawn to the elected species.
Priority
2. Application claims the benefit and priority of PCT/CA2021/051855 filed on 12/21/2021 which claimed the benefit and priority of provisional application 63/128,601 filed on 12/21/2020. Application is granted the benefit of provisional application 63/128,601 and the effective filing date of 12/21/2020.
Claim Rejections - 35 USC § 112
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.
3. Claims 1-2, 4-5, 7-10, 12-13, 30-33, 46, 48, 50, 53, 57-59 rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 is indefinite because it is drawn to a TCR construct comprising a constant alpha domain and constant beta domain, wherein the constant alpha and beta domains comprise stabilizing mutations comprising a first interchain disulfide bond between the constant alpha domain and constant beta domain and one or more stabilizing mutations selected from (a)-(v) and wherein the TCR construct has an increased TCR melting temperature as compared to a corresponding TCR construct comprising the first disulfide bond alone. This claim is indefinite because it does not identify the first interchain disulfide bond that if present alone would provide a comparison for the TCR melting temperature of the claimed TCR construct.
Claims 2 and 4 are indefinite because although it offers defined first interchain disulfide bonds between the constant alpha and beta chains of options (a)-(i), options (a) and (c)-(i) of claim 2 and (a) and (b) of claim 4 are also options in claim 1 for the other stabilizing mutations. If a TCR construct included two of these stabilizing mutations, it would be unclear which was the first interchain disulfide bond between the constant alpha and beta domains to compare the TCR construct for melting temperature.
Claim 59 is indefinite because it recites specific combinations of stabilizing mutations without identifying the first interchain disulfide bond and each option listed (a)-(e) include multiple mutations included in the list of potential first interchain disulfide bonds from claim 2.
Examiner suggests amending claim 1 according to the suggestions included with the 112(a) written description rejection to overcome the 112(b) indefiniteness rejection.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
4. Claims 1-2, 4-10, 12-13, 30-33, 46, 48, 50, 53, and 57-59 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a WRITTEN DESCRIPTION rejection.
The claims are drawn to a TCR construct comprising a TCR alpha chain polypeptide and a TCR beta chain polypeptide, the TCR alpha chain polypeptide comprising a variable alpha domain and constant alpha (Cα) domain and the TCR beta chain polypeptide comprising a variable beta domain and a constant beta (Cβ) domain, wherein the Cα domain and the Cβ domain comprise stabilizing mutations, the stabilizing mutations comprising a first interchain disulfide bond between the Cα and Cβ and one or more stabilizing mutations, the one or more stabilizing mutations selected from options (a)-(v) and wherein the TCR construct has an increased TCR melting temperature (Tm) as compared to a corresponding TCR construct comprising the first disulfide bond alone.
Thus, the claims identify the TCR construct by the function of stabilizing the TCR and increasing the Tm of the TCR construct as compared to a corresponding TCR construct with a first disulfide bond alone with the partial sequence structure of the TCR Cα and Cβ chains comprising a first interchain disulfide bond between the Cα and Cβ chains and one or more additional stabilizing mutations from the options of (a)-(v).
The specification identifies two interchain disulfide bonds that alone stabilized the TCR and provided a low Tm for comparison with the TCR constructs including additional stabilizing mutations, TRAC84 and TRBC 79, also referred to throughout the examples as the “IC disulfide” and TRAC 84.2 and TRBC 79. The specification also identifies the combination of the TRAC 84.2 and TRBC 79 disulfide bind and the TRAC-hinge disulfide bond (represented by option (a) in the claims) as providing a stabilized TCR construct in combination with three or more other stabilizing mutations. (See Example 11).
PNG
media_image1.png
208
658
media_image1.png
Greyscale
The specification uses the TCR construct with an “IC disulfide” of TRAC 84 and TRBC 79 alone as comparison for Tm for the other TCR constructs in Examples including (See Table 8.1, pg. 97 [00306]).
PNG
media_image2.png
126
661
media_image2.png
Greyscale
The specification identifies in Table 11 specific combinations of mutations that increase the temperature from the Tm of the IC disulfide. The specification further provides that certain combinations of mutations were unsuccessful. (pg. 96 [00304], copied below).
PNG
media_image3.png
96
656
media_image3.png
Greyscale
Thus, the instant specification discloses two distinct first interchain disulfide bonds that allow for a stabilized TCR construct that one or more other specific additional stabilizing mutations can be added and allow for an increase in Tm over a TCR construct with the IC disulfide alone. The instant specification also provides a TCR construct with two interchain disulfide bonds that stabilize a TCR construct and allow for three or more specific additional stabilizing mutations to be added and allow for an increase in Tm over a TCR construct with the IC disulfide alone.
To provide adequate written description and evidence of possession of the claimed TCR construct genus, the instant specification can structurally describe representative TCR construct variants that function to increase the Tm of the construct as compared to a TCR construct comprising one disulfide bond alone, or describe structural features common to the members of the genus, which features constitute a substantial portion of the genus. Alternatively, the specification can show the claimed invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics (see University of California v. Eli Lilly and Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997) and Enzo Biochem, Inc. V. Gen-Probe Inc.). A disclosure that does not adequately describe a product itself logically cannot adequately describe a method of using that product.
In this case, the only factor present in the claims is a recitation of the stabilizing mutations increasing the Tm as compared to a corresponding TCR construct comprising the first disulfide bond alone and a selection of stabilizing mutations that can be combined with a first interchain disulfide bond. The instant specification fails to describe structural features common to the members of the TCR construct genus, which features constitute a substantial portion of the genus because the instant specification fails to disclose representative TCR constructs that function as claimed. A definition by function does not suffice to define the genus because it is only an indication of what the TCR construct does, rather than what it is. Other than the specific combinations of TCR constructs disclosed through Table 11 that increase the TCR Tm as compared to a TCR comprising the IC disulfide bond alone, the specification fails to provide the TCR construct structural mutations coupled to the claimed functional characteristics. As evidenced by Froning et al. (Nature Communications, 2020, 11:2330), numerous possibilities for stabilizing mutations exist between the Cα and Cβ chains of the TCR alpha and beta chains with Froning providing seven additional stabilizing mutations not included in the present claims that increase the Tm of the TCR peptide chains. (See Froning, pg. 4 “Characterization of the seven stabilizing Cα/Cβ mutations”). The instant specification fails to describe a representative number of TCR construct variants for the genus of TCR constructs that function as claimed. Accordingly, in absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus required to make the claimed TCR constructs.
The claims broadly encompass a TCR construct comprising a Cα and Cβ domain with stabilizing mutations comprising a first interchain disulfide bond between the Cα and Cβ domains and one or more additional stabilizing mutations selected from the options of (a)-(v), wherein the TCR construct has increased the TCR Tm as compared to a TCR construct comprising the first disulfide bond alone. Applicants have not established any reasonable structure-function correlation with regard to the sequences in the Cα and Cβ domains that can be altered to provide a first interchain disulfide bond and provide a stabilizing mutation that allows for one or more stabilizing mutations from the list of (a)-(v) and increases the Tm as compared to the TCR construct that comprise the first interchain disulfide alone. Given the high number of amino acid sequences within the TCR Cα and Cβ domains the skilled artisan would not have been in possession with the vast repertoire of TCR constructs encompassed by the claimed invention. One could not reasonably or predictably extrapolate the structure of a single TCR construct comprising the Cα and Cβ comprising a first interchain disulfide bond and one or more additional stabilizing mutations selected from (a)-(v) that would allow for an increase in Tm for the TCR construct as compared to the TCR construct comprising the first disulfide bond alone. Therefore, one could not readily envision members of the broadly claimed genus.
Although Applicants may argue that it is possible to screen for TCR constructs that function as claimed, the court found in (Rochester v. Searle, 358 F.3d 916, Fed Cir., 2004) that screening assays are not sufficient to provide adequate written description for an invention because they are merely a wish or plan for obtaining the claimed chemical invention. “As we held in Lilly, “[a]n adequate written description of a DNA … ‘requires a precise definition, such as by structure, formula, chemical name, or physical properties,’ not a mere wish or plan for obtaining the claimed chemical invention.” 119 F.3d at 1566 (quoting Fiers, 984 F.2d at 1171). For reasons stated above, that requirement applies just as well to non-DNA (or RNA) chemical inventions.” Knowledge of screening methods provides no information about the structure of any future TCR constructs yet to be discovered that may function as claimed.
Given the lack of representative examples to support the full scope of the claimed variant TCR constructs, and lack of reasonable structure-function correlation with regards to the unknown variable interchain disulfide bonds between the Cα and Cβ chains that stabilize the TCR construct and allow for more additional stabilizing mutations to increase the Tm of the TCR construct, the present claims lack adequate written description. Thus, the specification does not provide an adequate written description of TCR constructs comprising stabilizing mutations that increase the TCR Tm that is required to practice the claimed invention.
Examiner Suggestion: Examiner suggests amending claim 1 to identify the first interchain disulfide bond as options (b) or (c) form claim 2, provide specific combinations of the additional stabilizing mutations of options (a)-(v) and define the “corresponding TCR construct comprising the first disulfide bond alone” to be the disulfide bond from claim 2(b).
5. Claim 53 is 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.
The factors to be considered in determining whether undue experimentation is required are summarized In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988). The court in Wands states: "Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is 'undue,' not 'experimentation.' " (Wands, 8 USPQ2d 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. "Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations." (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount or direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims.
The claims are drawn to a method of treating a disease or disorder in a subject by administering to the subject an effective amount of a TCR construct comprising an alpha chain polypeptide and a TCR beta chain polypeptide, the TCR alpha chain polypeptide comprising a variable alpha domain and a constant alpha domain and the TCR beta chain comprising a variable beta domain and a constant beta domain, wherein the Cα domain and Cβ domain comprise stabilizing mutations comprising a first interchain disulfide bond between the Cα and Cβ domains and one or more additional stabilizing mutations selected from options (a)-(v), wherein the TCR construct increase the Tm as compared to a TCR construct comprising the first disulfide bond alone.
Thus, the breadth of the claims is a broad TCR construct with no required epitope for binding.
The specification discloses the process of making and optimizing a TCR construct for stability and increased TCR melting temperature. The specification does disclose the use of the TCR constructs with additionally detailed information regarding the variable domains of the alpha and beta chains for treatment purposes. However, the specification fails to disclose any working examples of the TCR constructs comprising the stabilizing mutations in the constant domains alone as treating a disease without further detailing of the variable domain of the TCR.
Thus, the specification provides guidance and direction for designing a TCR construct that provides increased stability and Tm for the construct by introducing various stabilizing mutations in the Cα and Cβ domains but not for designing the variable domains for the treatment of a specific disease.
While the specification does provide working examples of the TCR constructs for treatment, the TCR construct used include specific Vα and Vβ domains with specific CDR regions that are not included in the present claims. The working examples require detailed structure that is not present as a limitation for the claimed invention. Thus, the working examples do not provide evidence that the claimed invention is sufficient for use as a treatment method.
Relevant art teaches that adoptive cell therapy using TCRs are an unpredictable art with success in some diseases and less efficacy with others. (Chandran, abstract) (Chandran et al., 2019, Immunological Reviews, 290:127-147). Chandran provides that while the constant region of the TCR is relatively known, the antigen binding region is comprised within the variable region that provides the specificity that is advantageous for cellular immunotherapy. (See Chandran pg. 129, section 2.2).
Thus, the nature of the invention is unpredictable that requires specialized techniques for designing effective TCR constructs for use in cellular immunotherapy.
The state of the art requires a skilled artisan to design specific sequences to bind to antigen to provide specificity for the TCR construct to be effective in treatment methods. The ordinary skilled artisan would not be able to practice the present claimed invention without undue experimentation, at a minimum it would require the skilled artisan to develop a TCR construct with a specific antigen binding sequence and test its effectiveness to bind and treat a specific disease process.
The state of the prior art indicates that the constant domains of the TCR are well known, but do not provide the specificity for the TCR constructs that makes the TCR useful in cellular immunotherapy.
The results of the outcomes are unpredictable with TCR immunotherapy working for some diseases like hematological cancers but showing weaker results with other diseases like solid tumors.
One cannot extrapolate the disclosure of the specification to the enablement of the claims because the breadth of the claims provides for a generic TCR construct without specified targeted domains that is required for A TCR construct to demonstrate specificity for treating a disease and the specification provides no guidance for how to make the TCR construct of the claimed invention functional for a specific disease and the state of the prior art demonstrates a highly unpredictable field where treatment for one disease using cellular immunotherapy is highly effective and another disease shows a weaker response.
Therefore, in view of the novel nature of the invention, what is unknown in the art because of the novel nature of the invention, the state of the art, the quantity of experimentation necessary, the breadth of the claims, lack of guidance in the specification, and the absence of working examples, it would require undue experimentation for one skilled in the art to practice the invention as broadly claimed.
Prior Art
6. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Sadio et al. (FEBS Letters, 2020, 594:477-490) discloses the introduction of novel intradomain disulfide bonds using cysteine mutations in the Cα and Cβ domains of the TCR while improving the stability of the construct and not affecting the antigen binding specificity. (See Sadio, abstract). It is not listed as a prior art because the mutations are all intradomain, whereas the present invention requires one stabilizing mutation that is interdomain, the mutations listed are all expressed in single constructs with no combinations of mutations, and none of the mutations listed are represented in the present claimed invention.
Conclusion
7. Claims 1-2, 4-10, 12-13, 30-33, 46, 48, 50, 53, and 57-59 are rejected.
8. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LINDSAY DUNN whose telephone number is (571)272-5825. The examiner can normally be reached Monday-Friday 8-4:30.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Samira Jean-Louis can be reached at 571-270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/LINDSAY DUNN/Examiner, Art Unit 1642
/Laura B Goddard/Primary Examiner, Art Unit 1642
Prosecution Insights