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 .
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Priority
The instant application, filed 09/16/2022, is a 371 filing of PCT/US2021/022641, filed 03/16/2021, which claims domestic benefit to US provisional application 62/990,396, filed 03/16/2020.
Status of Claims/Application
Applicant’s amendment of 01/08/2026 is acknowledged. Claims 42-44 are cancelled and claims 1-41 are currently pending.
Election/Restrictions
Applicant's election with traverse of the following species in the reply filed on 01/08/2026 is acknowledged.
Applicant was required to elect a single SAR structure. Applicant has elected the structure represented by SEQ ID NO: 16951, for which each component has been identified by applicant in the appendix of the election response.
Specifically, the SAR elected comprises two polypeptide chains, the first having a vHH linked to an antibody vH and the second lacking a first module with an antibody vL domain, both of which are attached to TCR constant chains, TM domains, and cytosolic signaling domains.
Applicant was required to elect a single antigen binding domain that correlates with the SAR. Applicant has elected vH and vL domains of SEQ ID NOs: 11081 and 10839, respectively, which bind to CD19, and an AABD of SEQ ID NO: 11531, which is a vHH domain that binds CD20.
Applicant was required to elect a single antigen from those recited in claims 16 and 39. Applicant has elected CD19 and CD20.
Applicant was required to elect a single therapeutic control for co-expression from those recited in claim 19. Applicant has elected K13, SEQ ID NO: 12005.
Applicant was required to elect a single sequence from claim 41 that corresponds with the structures elected in 1-3. Applicant has elected SEQ ID NO: 6261.
The traversal is on the ground(s) that the SAR claimed is patentably distinct from the SIR taught by WO’795. In the response, applicant argues that the SIRs disclosed in WO’795 do not feature an additional, non-scFv AABD positioned in front of a vH/vL or an scFv module on the same chain. Applicant argues that, in contrast, the claimed SAR includes a non-scFv AABD – such as a vHH nanobody or other single domain binder- attached via a linker at the N-terminus of a second module comprising vL, vH, Va/Vα, Vb1, Vb2, Vg, Vd, scFv, scTCR, Ig linker domain, or a combination thereof. Applicant argues that while WO’795 teaches multi-domain receptors, this is only in the form of separate chains, each bearing a single binding region, not two different antigen binding components on the same polypeptide chain or single receptor module in the manner of Applicant’s invention. Applicant provides Fig. 1 to highlight differences in the SIR of WO’795 compared to the SARs of the instant invention.
The arguments are not persuasive.
While the instantly claimed invention encompasses embodiments in which there are structural differences compared to the SIRs of WO’795, the instantly claimed invention also encompasses an embodiment in which the second module of the SAR is an Ig linker domain, indicating that the second domain is not required to be a separate antigen binding component. The instant disclosure identifies the “Ig linker domain” as including Ig linker domains (pages 66-67, [00188]), which overlap with the linkers taught by WO’795 for use in the SIR between the binding domain and the constant region (page 139, table 6D). For instance, WO’795 teaches that the linker can be IgCL, IgG1-CH1, IgG2-0C CH1, IgG2-IC CH1, IgG3 CH1, IgG4 CH1, IgAI CH1, IgA2 CH1, IgD CH1, IgE CH1, IgE CH1, and IgM CH1 (page 139, Table 6D), all of which meet the limitations of the instantly claimed Ig linker.
For these reasons, the requirement is deemed proper and is, therefore, made FINAL.
It is noted that the species election is made in order to reduce an unduly extensive and burdensome search necessary to search the entire scope of the claims. Upon identification of allowable subject matter, the election will be expanded to additional species.
In searches of the prior art, art that reads on the broader species of the second module comprising an Ig linker domain was identified. The election was expanded to include the use of an Ig linker domain as the second module and the art was subsequently applied.
As discussed in the election response, applicant has elected a SAR represented by SEQ ID NO: 16951 and a polynucleotide of SEQ ID NO: 6261, which comprise an AABD of SEQ ID NO: 11531, which is a vHH domain that binds CD20. In searches of the prior art, no vHH matching instant SEQ ID NO: 11531 was found. The election in claim 17 of SEQ ID NO: 11531, has been expanded to include the CD20 vHH of SEQ ID NO: 11589, and in claim 41 the election has been expanded to include the additional species of SEQ ID NO: 7347 for the purposes of applying prior art in an effort towards compact prosecution.
Claims 32-34, which are drawn to T cell fusion protein (TFP) structures, are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 01/08/2026.
Claims 1-31 and 35-41 are examined on the merits herein.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 09/16/2022, 10/30/2022, and 07/23/2024 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements have been considered by the examiner.
Specification Objections
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The specification contains the following embedded hyperlinks that comprise a prefix and/or other non-top level domain executable code (bolded for clarity):
Page 183, [00296]: https://jorgensen.biology.utah.edu/wayned/ape/
Page 318, [00796]: http://www.ejbiotechnology.info
The specification is objected to for the following informality: Table 11 on page 101, [00258], recites linkers with SEQ ID NOs: for the DNA and PRT. The last line recites the linker “G4Sx3” with a DNA SEQ ID NO: 1041 and a PRT SEQ ID NO: 11731. These sequences, however, are not sequences for a G4Sx3 linker nor do the sequences include the linker. The sequence are also recited at the end of table 10, where they are identified as CD8SP-BCMA-FHVH93-GS-ULBP2-S3. It appears that the line in the table was added in error. Appropriate correction/clarification is required.
Claim Objections
Claim 2 is objected to because of the following informality: the preamble of the claim recites “A recombinant polynucleotide encoding a SAR polypeptide of claim 1”. It is suggested that the preamble be amended to recite “The at least one recombinant polynucleotide encoding at least one SAR polypeptide of claim 1” for consistency with the other dependent claims and the wording of claim 1.
Claims 7 and 8 are objected to because of the following informality: the claims recite “transmbrane” in line 2 of each claim, which appears to be a misspelling of “transmembrane”. Appropriate correction is required.
Claim 8 is objected to because of the following informality: line 4, recites “at leasst 70%”. Correction of “leasst” to “least” is suggested.
Claim 15 is objected to because of the following informality: the claim recites the limitation “at least one epitope of one or more than antigen(s)”. The limitation appears to be missing the word “one” prior to “antigen(s)” at the end of the claim. Appropriate correction/clarification is required.
Claim 17 is objected to because of the following informality: part (iv), lines 1-2, and part (viii), lines 1-2, recite “SEQ ID NO: SEQ ID NOS:” correction to remove the redundant “SEQ ID NO:” recitations is suggested.
Claim 19 is objected to because of the following informality: The end of the claim recites “and combination thereof and combinations thereof”, which appears to be a redundant recitation. Appropriate correction is required.
Claims 33 and 34 are objected to because of the following informalities: the claims recite “claims 32” and “claims 33”, respectively. Correction from “claims” to “claim” is suggested.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-41 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 contains the trademark/trade names DARPIN, Adnectin, Fynomer, Alphabody, Centyrin, and Anticalin. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe a product and, accordingly, the identification/description is indefinite.
Claims 2-41 are rejected by virtue of their dependency on rejected claim 1 as they do not resolve the ambiguity discussed above.
Claim 1 recites a non-immunoglobulin antigen binding scaffold selected from the recited list which includes “an affilis” and “an pronecti”. These scaffolds are not art recognized scaffolds and they are not defined in the instant disclosure. As such, the metes and bounds of the claim are indefinite.
It is noted that these scaffolds may be misspellings for “affilin” and “pronectin”, which are also recited in the instant specification as potential AABD scaffolds.
Claims 2-41 are rejected by virtue of their dependency on rejected claim 1 as they do not resolve the ambiguity discussed above.
Claims 2 and 3 recite “Vb”. There is insufficient antecedence for this limitation in the claims. Claims 2 and 3 depend on claim 1, which, in part (b), recites “Vb1 (Vβ1), Vb2 (Vβ2)”. The claim does not recite a Vb. Additionally, in so far as the limitation could be interpreted as referencing Vb1 or Vb2, it is unclear which of the two are being referenced, or if both are being further limited. See MPEP 2173.05(e) which states “ if two different levers are recited earlier in the claim, the recitation of "said lever" in the same or subsequent claim would be unclear where it is uncertain which of the two levers was intended.“
Claim 6, line 2 recites “the encoded optional linker domain”. Claims 1 and 2, on which claim 6 depends, recite numerous optional linkers. For instance, claim 1 recites one or more optional linkers that can be used between the first, second, third, fourth, and/or fifth modules. Claim 2 recites optional linkers in both part 1) and 2). It is unclear what linker(s) are limited by the recitation in claim 6 rendering the metes and bounds of the claim indefinite. See MPEP 2173.05(e) which states “ if two different levers are recited earlier in the claim, the recitation of "said lever" in the same or subsequent claim would be unclear where it is uncertain which of the two levers was intended.“
Claim 15 depends on claim 1 and recites the limitation “the encoded two or more AABDs bind to: i) at least one antigen; and/or ii) at least one epitope of one or more than antigen(s)”.
There is insufficient antecedent basis for “the encoded two or more AABDs” in the claim. Claim 1 recites “one or more” AABDs and neither claims 1 nor 15 require there be two or more AABDs, rendering the metes and bounds of the claim indefinite. Additionally, it is unclear if, under the scope of the claims in which there is one AABD, if the AABD is limited by the recitations in claim 15 or not.
In the instant office action the claim is interpreted as applying to the one or more AABDs recited in claim 1.
Claim 17 recites antigen binding domains with sequence limitations recited in parts (i)-(xii). The end of each of parts (i)-(iv), (viii), and (xi)-(xii), the limitation “which encodes a polypeptide that binds to its antigen” is recited. Parts (vi) and (vii) recite “which encodes a polypeptide that binds to its cognate”; part (ix) recites “which encodes a polypeptide that binds to its adaptor”; and part (x) recites “which encodes a polypeptide that binds to its autoantibody or autoantibody producing cells”. These recitations render the claim indefinite as it is unclear what “its antigen”, “its cognate”, “its adaptor”, and “its autoantibody or autoantibody producing cells” is referencing. Specifically, it’s unclear what “its” references. For instance, the claims encompass a genus of antigen binding domains and it is unclear if “its” refers to the parent sequences that are recited or if “its” refers to any of the species within the claimed genus indicating that the binding domain could bind anything. As the metes and bounds of the claim are unclear, the claim is indefinite.
Additionally, part (x) of the claim recites an autoantigen comprising a sequence set forth in any one of “SEQ ID NO 11687, 22406-22407 to 11712 or 22383”. It is unclear what sequences are encompassed by the recitation “22406-22407 to 11712” rendering the metes and bounds of the claim indefinite. Additionally, not all sequences between 11712 and 22407 are autoantigens and the limitations “to 11712 or 22383” are also recited in (xi) where the sequences are identified as adaptor binding domains.
Appropriate correction is required.
Claim 18 depends on claim 1 and recites the limitation “wherein at least one of the target antigens is expressed on blood linage cells while at least one of the target antigens is expressed on solid tumor cells”. There is insufficient antecedent basis for the recitations of “the target antigens” in the claim rendering the metes and bounds of the claim indefinite. Additionally, claim 18 suggests the targeting of two target antigens (one expressed on blood linage cells and the other expressed on solid tumor cells); however, claim 1 does not necessarily require there be two target antigens. As such, it is unclear what is required by the claim.
In the instant office action, the claim is interpreted as requiring that the SAR target at least one antigen expressed on blood linage cells or on solid tumor cells.
Claim 38, line 3, recites “an immune effector cell of claim 22 any one of claims 22-35”. Based on the inclusion of two references to claims presented prior, with no conjunction between, it is unclear what claim(s) are being referenced in the limitation rendering the metes and bounds of the claim indefinite.
Claim Rejections - 35 USC § 112(a)
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.
Scope of Enablement
Claims 39-40 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating a disease, does not reasonably provide enablement for preventing a disease. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Enablement is considered in view of the Wands factors (MPEP 2164.01(a)). 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. While all of these factors are considered, a sufficient amount for a prima facie case are discussed below.
The nature of the invention
The instant invention is drawn to a method of preventing a disease associated with the expression of a disease-associated antigen in a subject, comprising administering to the subject an effective amount of a SAR polypeptide, where the SAR polypeptide binds to one or more disease associated antigens recited in claim 39. Claim 40 further limits the disease to being a proliferative disease, precancerous condition, cancer, and a non-cancer related indication associated with expression of the disease-associated antigen.
The breadth of the claims
The claims are broad in that they encompass prevention of any disease using any form of synthetic antigen receptor that binds to one of the disease associated antigens recited in claim 39.
The specification does not provide an explicit definition for “preventing” or “prevention”. In absence of a limiting definition by the applicants, “prevention” is interpreted as defined according to IIME as provided in Wojtczak, A. (2002) Glossary of Medical Education Terms Medical Teacher 24(4): 357; 1-25. IIME defines “prevention” as promoting health, preserving health, and to restore health when it is impaired, and to minimize suffering and distress (page 16, “Prevention”). IIME states that “primary prevention refers to the protection of health by personal and community wide effects, such as preserving good nutritional status, physical fitness, and emotional well-being, immunizing against infectious diseases, and making the environment safe.” IIME states that “secondary prevention can be defined as the measures available to individuals and populations for the early detection and prompt and effective intervention to correct departures from good health”. IIME further states that tertiary prevention consists of the measures available to reduce or eliminate long-term impairments and disabilities, minimize suffering caused by existing departures from good health”.
Thus, in its broadest reasonable interpretation, the prevention of a condition suggests that that the onset of the condition never occurs and the patient’s health is protected and preserved.
The amount or direction provided by the inventor / the existence of working examples
The examples of the instant disclosure demonstrate the construction of various SARs, lentiviral and retroviral vectors encoding the SARs, and infection of T cells and PBMCs with the vectors (pages 323-370). The examples also disclose various cell lines engineered to express luciferases for measuring cytotoxicity of the SARs (page 321). In the examples, SAR constructs were expressed in T cells and tested for in vitro cytotoxicity against cell lines expressing the target antigens and are shown to have antitumor activity ([00895]-[00896]). Additional examples tested T cells expressing SARs in mouse models. In the models, cancer cells were implanted subcutaneously and, seven days later, SAR T cells were injected and demonstrated cytotoxicity compared to controls that had progressive tumor growth ([00944]-[00945]). Examples are also provided detailing methods that can be used for autologous or allogeneic SAR-T cells for adoptive cell therapy in patients ([00956-[00969]) or in mice ([00971]-[00974]).
The disclosure does not identify, or demonstrate through working examples, a method that could be used by one of ordinary skill in the art to predictably determine that a subject would develop a disease associated with the recited antigens in order to establish that cancer was prevented using the claimed method.
The state of the prior art / the level of predictability in the art
There are no art recognized methods that can be used to predictably determine that disease onset, such as cancer, was prevented using claimed method or to identify patients who would predictably develop such a disease in order to predictably identify that prevention was achieved using therapeutic approaches. Rather, the state of the art indicates that disease, particularly cancer, development was not predictable.
Lewandowska, A.M., et al (2017) Environmental risk factors for cancer – review paper Ann. Agric. Environ. Med. 26(1); 1-7 teaches that the cancerous process is a result of disturbed cell function. This is due to the accumulation of many genetic and epigenetic changes within the cell, expressed in the accumulation of chromosomal or molecular aberrations, which leads to genetic instability. It is difficult to assess the validity of individual etiological factors, but it can be concluded that interaction of various risk factors has the largest contribution for the development of cancer. Environmental, exogenous and endogenous factors, as well as individual factors, including genetic predisposition, contribute to the development of cancer (page 1, right column, paragraph 1). Lewandowska discusses numerous factors that contribute to the development of cancer including physical factors such as exposure to electromagnetic fields, ionizing radiation, and ultraviolet radiation (pages 2-3); chemical factors including tobacco smoking, alcohol, and other chemicals (pages 3-4); and biological factors including diet, physical activity, mutagenic and carcinogenic compounds in food, nitrosoamines, and infections (pages 4-5). Lewandowska teaches that, additionally, some epidemiological research suggests that the influence of environmental factors will further affect the cell’s genetic material. This is connected with the spreading of carcinogens in various geographical zones. While some are well known and can be modified, there are certain factors that cannot be fully controlled, such as industrialization (page 6, left column, paragraph 2).
The teachings of Lewandowska demonstrate that, while it was known that cancer is caused by disturbed cell function, numerous factors had been identified that could lead to such disfunction and cell disfunction is likely caused by the interaction of various risk factors. Lewandowska also teaches factors such as genetic predisposition and environmental factors that can contribute to the formation of cancer but are beyond the control of an individual subject. These teachings demonstrate that there was no specific known cause of cancer and, therefore, suggest that there would be no method to predictably determine that cancer would have developed in order to establish that it was prevented.
Cuzick, J. (2017) Preventive therapy for cancer Lancet Oncol 18; e472- e482 teaches the use of therapeutic preventative measures in addition to weight control and physical activity, such as low-dose aspirin for adults without the risk of hypertension or gastrointestinal bleeding, universal HPV vaccination, and other therapies such as anti-oestrogen drugs for breast cancer prevention targeting high-risks groups to “maintain a favorable benefit-risk ratio” (abstract). While Cuzick is identifying therapeutic regimens to prevent cancer, Cuzick also teaches “the balance of risks and benefits is inherently more challenging for preventative than for therapeutic interventions. Only a small fraction of the apparently healthy people who receive a preventative treatment would ultimately develop the specific type of cancer being targeted. Moreover, the absence of the cancer is not quantifiable at an individual level, whereas all those treated will incur a risk of side-effects which are identifiable on an individual basis” (page e472, left column, paragraph 2).
Cuzick demonstrates that the prevention of cancer is not predictable and that numerous factors contribute to the development of cancer. Additionally, Cuzick teaches difficulties in preventing cancer with therapeutic methods and specifically states that the absence of cancer is not quantifiable on an individual level, a statement which demonstrates that the determination of whether or not cancer was prevented is unpredictable.
DeCensi, A., et al (2015) Barriers to preventative therapy for breast and other major cancers and strategies to improve uptake ecancer 9(595); 1-12 teaches that the global cancer burden continues to rise but the utilization of preventative therapy has been poor due to various barriers. DeCensi teaches barriers such as the lack of physician and patient awareness, fear of side effects, and licensing and indemnity issues. DeCensi provides a review discussing the barriers and proposes strategies to overcome them including improving awareness and countering prejudices by highlighting the important differences between preventative therapy and cancer treatment. DeCensi further teaches that future research to improve therapeutic cancer prevention needs to include improvements in the prediction of benefits and harms and improvements in safety profiles of existing agents by experimentation with dose (abstract). DeCensi teaches that for preventative therapy, we cannot identify individuals whose cancer was prevented or risk was substantially reduced because of the lack of measurable biomarkers of efficacy that currently exist for other diseases such as cardiovascular diseases, prevention of diabetes complications or osteoporotic bone fractures. Therefore, from that person’s point of view, they either took medication unnecessarily or, in the worst-case scenario, unnecessarily suffered the adverse effects of such therapy (page 2, paragraph 1).
The teachings of DeCensi demonstrate that, while preventative therapies could be beneficial if various barriers are overcome, there was no method known that could be used to identify individuals whose cancer was prevented because of the lack of measurable biomarkers.
The teachings of Lewandowska, Cuzick, and DeCensi demonstrate that there was no art recognized method of determining whether a subject would predictably develop cancer and, therefore, there is no predictable way to determine that cancer was prevented using the claimed method.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure
As discussed above, there is no disclosed or art recognized method through which an ordinarily skilled artisan would be able to determine that a subject would have predictably developed a disease such as cancer in order to apply the claimed treatment as a preventative measure. Furthermore, there is no known or disclosed method that could be used to establish that cancer was prevented as there is no predictable way to know that the subject being treated would have developed a disease without the treatment. As such, in order to implement the invention as claimed, one of ordinary skill in the art would have to participate in undue experimentation to identify a method that could be used to establish that cancer was prevented, with the possibility that no such method could be found.
In view of the Wands factors discussed above, a person of ordinary skill in the art would have to engage in undue experimentation to practice the full scope of the claimed invention. As such, the instant claims were determined to not meet the scope of enablement requirement of 35 USC 112(a).
Written Description
Claims 17 and 41 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.
Instant claim 17 is drawn to an encoded SAR polypeptide comprising one or more antigen binding domains selected from those recited in (i)-(xii).
Parts (i)-(xii) of the claim recite a genus of binding domains all of which are claimed to function as antigen binding domains and to bind to its antigen/cognate, adaptor, or autoantibody/autoantibody producing cells.
Specifically, part (i) recite a vH comprising a sequence set forth in any of SEQ ID NOs: 10978-11214 and encompasses sequences with at least 70% identity to these vH sequences as well as sequences with at least 70% identity to the three CDRs set forth in any one of SEQ ID NOs: 10978-11214 and 23148-23161, sequences with less than 3 substitutions in the CDRs, and sequences that bind to the same target antigens or the same epitopes on the target antigens as the sequences set forth. Thus, claim 17 part (i) encompasses a genus of antigen binding domains in which any of the vH claimed can be paired with any vL and can have modifications anywhere in the vH, including in the CDRs. The claim also encompasses a genus of binding domains that are only required to bind the same target antigen or the same epitopes on the target antigens as binding domains comprising the recited vH.
Part (ii) of the claim recites similar limitations, but for the vL region and also encompasses a genus of antigen binding domains in which any of the vL claimed can be paired with any vH and can have modifications anywhere in the vL, including in the CDRs. The claim also encompasses a genus of binding domains that are only required to bind the same target antigen or the same epitopes on the target antigens as binding domains comprising the recited vL.
Part (iii) recites a scFv comprising a sequence set forth in any one of SEQ ID NOs: 11220-11456 or sequences with 70% identity thereto and which encodes a polypeptide that binds to its antigen. As such, the limitation encompasses a genus of scFvs in which modifications up to 70% identity can be made anywhere in the scFv.
Part (iv) recites camelid VHH domains comprising a sequence as set forth in any one of the recited SEQ ID NOs, or sequences with at least 70% identity to the sequences recited, or sequences with at least 70% identity in the CDRs in the sequences recited, or sequences with less than 3 substitutions in the three CDRs of the sequences recited, or sequences that bind to the same target antigens or the same epitopes on the target antigens as the sequences set forth, which encodes a polypeptide that binds to its antigen. Thus, claim 17 part (iv) encompasses a genus of scFvs that can have modifications anywhere, including in the CDRs. The claim also encompasses a genus of scFvs that are only required to bind the same target antigen or the same epitopes on the target antigens as the scFvs recited.
Part (v) encompasses non-immunoglobulin scaffolds encoded by a polynucleotide recited, or sequences with at least 70% identity to those recited, or sequences that bind to the same target antigens or the same epitopes on the target antigens as the sequences recited. The claim encompasses non-immunoglobulin scaffolds in which variation can be made anywhere within the scaffold up to 70% identity as well as scaffolds that bind the same target antigens or epitopes as those encoded by the recited sequences.
Parts (vi) and (vii) encompass ligand binding domains of a receptor or receptor binding domains of a ligand with at least 70% identity to the sequences recited and which encode a polypeptide that binds to its cognate. Such limitations encompass a genus of binding domains with variation anywhere in the ligand binding domain or receptor binding domain.
Part (viii) recites a single vH comprising a sequence as set forth in any of those recited, or sequences with at least 70% identity with the recited sequences, or sequences with 70% identity in the CDRs of the recited sequences, or sequences with less than 3 substitutions in the three CDRs, or sequences that bind to the same target antigens or the same epitopes on the target antigens. Thus, claim 17 part (viii) encompasses a genus of single vH that can have modifications anywhere, including in the CDRs. The claim also encompasses a genus of single vH that are only required to bind the same target antigen or the same epitopes on the target antigens as the single vH recited.
Part (ix) recites an adapter binding domain comprising a sequence recited as well as those with at least 70% identity thereto. Thus the claim encompasses a genus of binding domains with variation anywhere in the adapter binding domain up to 70% identity.
Part (x) recites an autoantigen comprising a sequence recited or sequences with at least 70% identity thereto. Thus the claim encompasses a genus of autoantigens with variation anywhere in the autoantigens up to 70% identity.
Part (xi) recites a TCR variable region comprising a sequence set forth in the claim or sequences with at least 70% identity thereto, or sequences with at least 70% identity in the three CDRs of the recited sequences, or sequences with less than 3 substitutions in the CDRs or sequences that bind to the same target antigens or the same epitopes on the target antigens. Thus, claim 17 part (xi) encompasses a genus of TCR variable regions that can have modifications anywhere, including in the CDRs. The claim also encompasses a genus of TCR variable regions that are only required to bind the same target antigen or the same epitopes on the target antigens as the TCR variable regions recited.
Part (xIi) recites a single TCR domain comprising a sequence set forth in the claim or sequences with less than 3 substitutions in the CDRs or sequences that bind to the same target antigens or the same epitopes on the target antigens. Thus, claim 17 part (xii) encompasses a genus of single TCRs that can have modifications anywhere, including in the CDRs. The claim also encompasses a genus of single TCRs that are only required to bind the same target antigen or the same epitopes on the target antigens as the single TCRs recited.
Furthermore, each of the parts (i)-(xii) recite “a sequence as set forth in any”, in the broadest reasonable interpretation of “a sequence” the claim encompasses sequences that comprise only portions of the recited sequences including those with as little as two matching amino acids.
Claim 41 recites a recombinant polynucleotide encoding a SAR polypeptide where the polynucleotide is selected from the group recited or a sequence with at least 75% identity to the nucleotide sequences recited. The claim is therefore, drawn to a genus of polynucleotides all of which are claimed as functioning as a SAR.
As such, the claims are drawn to a genus of binding domains all of which are claimed to have functions in binding.
The instant disclosure, however, does not provide a representative number of species of the claimed antigen binding domains nor does the disclosure provide a structure-function correlation that would allow an ordinarily skilled artisan to predictably identify which species of the claimed genus would perform the functions as claimed.
The instant disclosure provides sequences for binding domains on pages 86-101. The disclosure does not provide any species in which modifications are made to the disclosed binding domains such that the resulting binding domain comprises 70% identity, has variation in the CDRs, or comprises fragments of the recited sequences. Additionally, the specification does not provide any epitope data for the binding domains nor does the disclosure provide any species of binding fragment that bind the same epitopes as those recited in the instant claims.
The binding domains disclosed with 100% identity represent the binding domains that applicant was in possession of at the time of the effective filing date. Particularly, in the cases of antibodies, VHH, scFvs, etc. applicant has only demonstrated possession of those with a full complement of 6 CDRs (in cases where there is a vH and vL) or 3 CDRs (for VHH or single vH domains).
The instant disclosure also does not provide a structure-function correlation that would allow an ordinarily skilled artisan to make modifications in the disclosed binding domains while maintaining binding function.
The prior art also does not provide a representative number of species of the claimed genus nor does the prior art provide a structure-function correlation that would allow for the predictable modification of the claimed binding domains. Rather, the art suggests that, particularly in the case of antibodies and TCRs, structure and function were not predictable.
For instance, Chiu, M.L., et al (2019) Antibody structure and function: The basis for engineering therapeutics Antibodies 8(55); 1-80 teaches that, the antigen-binding site of immunoglobulins is formed by the pairing of the variable domains (VH and VL) of the Fab region. Chiu teaches that each domain contributes three complementarity determining regions (CDRs), specifically, three from the VL and three from the VH, and that the six CDR loops are in proximity to each other resulting from the orientation of the VL and VH regions. Chiu teaches that the configuration of the VL and VH brings the three CDRs of the VL and VH domains together to form the antigen-binding site (page 4, paragraph 2).
These teachings of Chiu demonstrate that the interaction between the heavy and light chain variable domains effect the conformation of the binding region of the antibody and therefore the antibody’s ability to bind to its target. Furthermore, the teachings of Chiu point out that the binding site is formed by the combination of the heavy and light chain CDRs (six regions) together. Based on these teachings, an ordinarily skilled artisan would not have been able to predictably identify which species of the instantly claimed genus would be capable of performing the claimed function. This is particularly the case in the absence of a full complement of heavy and light chain CDRs.
Hoey, R.J., et al (2019) Structure and development of single domain antibodies as modules for therapeutics and diagnostics Experimental biology and medicine 244; 1568-1576 teaches that VHH domains typically rely heavily on CDR3 for interactions with antigens. Notably, an elongated CDR3 loop provides VHH significant versatility in its ability to interact with target molecules. Unlike conventional antibodies, VHH domains have been observed to interact with antigens in protruding/extended conformations, which allow the antibody to bind protein clefts/pockets, including enzyme active sites. In addition, the CDR3 loop can produce a structurally flat paratope using CDR1/3, CDR1/2/3, and CDR2/3/FW, with some possessing more convex or concave paratopes (paragraph bridging columns, page 1569).
The teachings of Hoey demonstrate that for single domain antibodies, such as VHH, binding depends on the full complement of three CDRs.
Wong, W.K., et al (2019) Comparative analysis of the CDR loops of antigen receptors Frontiers in immunology 10(2454); 1-11 teaches that for both antibodies and TCRs, the main determinants of target recognition are the complementarity-determining region (CDR) loops. Five of the six CDRs adopt a limited number of backbone conformations, known as the “canonical classes”; the remaining CDR (β3 in TCRs and H3 in antibodies) is more structurally diverse (abstract). In TCRs, CDR1 and CDR2 typically contact the MHC’s conserved α-helices, while the CDR3 almost always contacts the peptide antigen. The structural complementarity between the binding sites of the antigen receptor and their cognate antigen governs the binding interactions. As the CDRs form the majority of the binding site, their conformations are critical to the binding (page 2, left column, paragraph 1).
Wong studied canonical forms in TCRs and built an auto-updating sequence-based prediction tool and compared TCR CDRs to antibody CDRs (abstract). Wong teaches that the fact that nearly 20% of the TCR CDRs that could show different conformations did so, suggests that the canonical class model will struggle to accurately predict TCR CDR conformations (page 7, right column, paragraph 5).
Wong demonstrates that, like antibodies, TCRs depend on a full complement of CDRs for binding.
With regards to epitope binding, the art demonstrates that epitope binding based on structure alone was not predictable.
For instance, Hummer, A.M., et al (2022) Advances in computational structure-based antibody design Current Opinion in Structural Biology 74(102379); 1-7, herein “Hummer”, teaches that traditional methods for antibody development, such as deriving antibodies from hybridomas of inoculated animals or from library assembly followed by display techniques are not only costly and time consuming but also are not necessarily able to produce antibodies that bind to the desired site (epitope) on an antigen. Hummer teaches that computational antibody design methods offer a way to overcome these limitations, but are held back by the lack of accurate antibody and antigen structures (page 1, right column, paragraph 2). Hummer provides a review on how advances in protein structure prediction and other areas are bringing us closer to being able to entirely computationally designed antibodies that bind strongly to a defined epitope (page 1, right column, paragraph 3) demonstrating that in 2022 predictable structure function relationships were still not known. Hummer acknowledges this in their discussion of future directions stating that “Several challenges still remain for true computational structure-based antibody design. While there has been great progress in protein structure prediction, current methods are not yet able to accurately predict the position of the side chain atoms or structural changes on binding. For antibodies, accurately modeling the CDR-H3 loop remains a major obstacle. Additionally, improvements in paratope and epitope prediction, both in terms of accuracy and specificity (predicting the types of binding interactions for residues), will be needed to help improve docking for high-throughput virtual screening.” (page 4, right column, paragraph 3).
Hummer teaches the difficulties in predicting the relationship between antibody structure and the epitopes to which they bind demonstrating a lack of predictability in the field between antibody structure and function.
Neither the disclosure, nor the prior art, provide a representative number of species of the genus of antigen binding domains claimed performing the functions of binding to an antigen, cognate, adaptor, or autoantibody/autoantibody producing cells. The disclosure also does not provide a structure-function correlation that could be used to identify which species of the instant claims would be capable of performing the claimed functions. The prior art also does not provide a representative number of species and suggests that structure-function of binding domains is not predictable.
Therefore, instant claims 17 and 41 were found not to meet the written description requirement of 35 USC 112(a).
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 39-40 are rejected under 35 U.S.C. 102 (a)(1) as being anticipated by Mohanty, R., et al (2019) CAR T cell therapy: A new era for cancer treatment (Review) Oncology Reports 42; 2183-2195.
Mohanty teaches that chimeric antigen receptors (CARs) are unique receptors that are designed to target specific tumor antigen to functionally reprogram T lymphocytes. Mohanty teaches that T lymphocytes are genetically engineered to express these artificial receptors to target cancer cells (paragraph bridging pages 2183-2184). CARs are an emerging immunotherapy for several malignancies. This therapeutic approach is an experimental form of gene therapy that redirects T lymphocytes to eradicate cancer cells (page 2184, left column, 2. CAR T cell therapy). CAR T cell therapy reconfigures T lymphocytes with an antibody specific-scFv fragment obtained from monoclonal antibodies by replacing different parts of the TCRα and β chains. Depending on the diverse biomarker selection and structural complexity, different generations of CAR models have been developed (page 2184, right column, paragraph 1), including first, second, third, and fourth generation CARs (pages 2184-2185; Fig. 2). There are also advanced models of CAR T cells including tandem CARs, bispecific CARs, physiological CARs, Universal CARs, and iCAR (page 2188, Fig. 3).
Mohanty provides a list of CAR therapy clinical trials in Table 1 (page 2191). The table shows treatment of a variety of different cancers using CARs that target CD19, CD20, CD22, CD19/CD20, CD19/CD22, CD133, CD171, PMSA, CEA, HER-2, CD30, FAP, NKGD2, GD2, EGFRVIII, Mesothelin, CD38/CD123, ROR1, MUC16, GPC3, or VEGFRII.
The most notable advantage of CAR T cell therapy over other cancer therapies is the abrupt time intervention and single infusion of CAR T cells. Clinical trials on blood cancers have shown that, even in patients with a refractory condition in which cancer reverted following several transplants, CAR T cell therapy was successful in completely eradicating the disease. Additionally, with CAR T cells, patients can live life without the risk of relapse and benefit from a sanatory treatment, such as stem cell transplantation (paragraph bridging pages 2190-2191).
Several clinical trials are currently examining the use of CAR T cell therapy against solid tumors and other diseases. Reports suggest that mesothelin-specific CAR mRNA engineered T cells can induce antitumor activity in solid malignancies. Furthermore, CAR technology has been used in organ transplantation using two novel HLA-A2 specific CARs, one representing a CD28-CD3d signaling domain and the other missing an intracellular signaling domain. CARs comprising ICOS signaling domain liases with the effective antitumor effect on EGFRvIII expressing glioma. The preclinical targeting of 5T4 in ovarian cancer has been associated with a successful outcome. An unexpected evolutionary finding was reported during the investigation of CAR targeting autoimmune diseases (paragraph bridging columns, page 2191). Mohanty also teaches that CAR T cell therapies have been approved by the FDA (page 2192, 9. Success rates of approved therapies).
The CAR T cells taught by Mohanty meet the instant claim limitation of an immune effector cell comprising a SAR polypeptide based on the definition of SAR in the instant disclosure. The instant specification, page 72, [00212], defines “Synthetic Antigen Receptor” or “SAR” as referring to “a non-natural polypeptide, which when expressed in an effector cell, provides the cell with specificity for a target cell, typically a cancer cell. SARs are engineered receptors that graft an antigen specificity onto cells (e.g., T cells, NK cells, NKT cells, monocytes/macrophages, B lymphocytes or combination thereof) thus combining the antigen binding properties of the antigen binding domain with the effector function of the cells... SAR, as the term is defined herein, covers first generation CARs, 2nd generation CARs, 3rd generation CARs, and next generation CARs…”
Thus, Mohanty anticipates claims 39 and 40.
Claims 41 is rejected under 35 U.S.C. 102 (a)(1) as being anticipated by WO 2018/102795 A2 (Chaudhary, P.M.) 07 June 2018.
US’795 teaches synthetic immune receptors (SIRs), nucleic acids encoding the SIRs, methods of making the SIRs, and the use of the SIRs in adoptive cell therapy (abstract). US’795 teaches SIRs and CARs targeting CD19 containing different antigen binding domains in Table-10C, including the following:
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US’795, SEQ ID NO: 11245, is identical to instant SEQ ID NO: 7347. The alignment results from ABSS demonstrating a 100.0% match are shown below.
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Thus, US’795 anticipates instant claim 41.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-28, 35, and 38-40 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2018/102795 A2 (Chaudhary, P.M.) 07 June 2018.
WO’795 teaches synthetic immune receptors, nucleic acids encoding the SIRs, and methods of making and using the SIRs, in, for example, adoptive cell therapy (abstract).
WO’795 teaches at least one recombinant polynucleotide encoding at least one synthetic immune receptor (SIR), the at least one SIR comprising:
(1) a TCR constant chain;
(b) an optional linker; and
(c) one or more non-natural TCR antigen binding domains comprising an antibody; an antibody fragment; a vH domain; a vL domain; a single chain variable fragment (scFv); a single domain antibody SDAB); a camelid VHH domain or a fragment thereof; a monomeric variable region of an antibody; a non-immunoglobulin scaffold such as a DARPIN, an antibody, an affilin, an adnectin, an affitin, an obodies, a repebody, a fynomer, an alphabody, an avimer, an atrimer, a centyrin, a pronectin, an anticalin, a kunitz domain, an armadillo repeat protein, or a fragment thereof; a receptor or a fragment thereof; a ligand or a fragment thereof; a bispecific-antibody, antibody fragment, scFv, vHH, SDAB, non-immunoglobulin antigen binding scaffold, receptor or ligand; and an autoantigen or fragment thereof (pages 349-350, claim 1).
WO’795 teaches that the SIR comprises an antigen binding domain and one or more T cell receptor constant regions, where the antigen binding domain binds to a target antigen including antigens that overlap with those recited in the instant claims (pages 96-99, [00205]). WO’795 teaches antigens including CD19 and CD20, and exemplifies SIRs targeting one or both of these antigens (page 307-310).
WO’795 further teaches that the nucleic acid sequence of the SIR comprises a fusion with the extracellular domain, transmembrane domain, and cytosolic domain of human CD3zeta (page 95, [00200]). WO’795 also teaches that each chain of the SIRs have a general structure of Signal peptide- binding domain-optional linker-T cell receptor constant region – optional accessory molecule. The T cell receptor constant region ay comprise a fusion between a T cell receptor constant chain and a CD3 signaling chain with an optional co-stimulatory domain (page 78, [00149]).
WO’795 teaches that the TCR is a heterodimer of an alpha (α) and a beta (β) chain.
The β chain has two isoforms: cβ2 (in 80% of human T cells) and Cβ1 (in 20% of human T cells). Each chain of the TCR comprises an N-terminal immunoglobulin (Ig)-like variable (V) domain and an lg-like constant (C) domain, which in turn comprises a transmembrane region and a short cytoplasmic tail at the C-terminus (page 2, [0009]).
WO’795 further teaches that the one or more non-natural TCR antigen binding domain(s) are optionally connected to each of the TCR constant regions by a linker region, wherein the linker region comprises a nucleic acid that encodes an amino acid sequence selected from the group consisting of SEQ ID NOs: 2981-3003, and any combinations thereof (page 384, claim 136). These linkers correspond to linkers disclosed in table 6D (page 139, [00284]), and include linker domains such as IgCL, IgG1-CH1, IgG2-0C CH1, IgG2-IC CH1, IgG3 CH1, IgG4 CH1, IgAI CH1, IgA2 CH1, IgD CH1, IgE CH1, IgE CH1, and IgM CH1. These linker domains meet the instant claim limitation of an Ig linker domain based on the instant disclosure which identifies these domains as Ig linker domains (instant spec, pages 66-67, [00188], claim 5 and table 13, pages 103-104).
WO’795 provides depictions of various forms that the SIRs of the disclosure can have upon expression including those in Fig. 5A-Q (shown below). In the constructs, SIRs are based on a single domain antibody (VHH) which bind to only one of the two TCR constant chains and the other chain is left empty. WO’795 teaches that similar constructs can be made that are based on other non-immunoglobulin binding domains instead of a VHH domain, including those based on affibodies, DARPINs, autoantigens, ligands, or receptors (page 42, [0036]; Fig. 5A-Q).
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As shown, the SARs comprise VHH attached to the N-terminus of a first or second polypeptide chain comprising TCR constant chains.
WO’795 teaches that the SIRs disclosed engage the full force of physiological T cell receptor signaling pathway (page 48, [0057]). WO’795 further teaches that the signaling domain is a functional region that transmits information within the cell to regulate cellular activity via defined signaling pathways by generating second messengers or functioning as effectors by responding to such messengers (page 74, [00138]).
WO’795 further teaches double chain SIR formats (page 70, 00121).
WO’795 further teaches that the vector or mRNA encoding the SIR may encode for additional genes/proteins including therapeutic controls, inhibitory molecules, accessory molecules, etc., including accessory molecules that overlap with those recited in the instant claims (page 371, claim 99; page 228, [00363]). WO’795 teaches that the accessory molecules are agents that enhance the activity of a SIR-expressing cell. Examples of accessory molecules that comprise of agents that can enhance the activity of a SIR-expressing cell are provided in Table 8. The agents disclosed include K13, FKBP-K13, and FKBPX2-K13, which are disclosed to provide costimulatory signal to SIR (page 228, [00363]).
WO’795 further teaches at least one vector comprising the recombinant polynucleotie described, where the vector is selected from the group consisting of a DNA vector, an RNA vector, a plasmid, a lentivirus vector, an adenoviral vector, a retrovirus vector, a baulovirus vector, a sleeping beauty transposon vector, and a piggybac transposon vector (pages 18-19, [0012]).
WO’795 teaches at least one polypeptide encoded by the at least one recombinant polynucleotide (page 19, [0013]) as well as a recombinant cell that expresses the at least one recombinant polynucleotide (page 19, [0014]). WO’795 further teaches that the cell is an immune effector cell, a stem cell that can give rise to an immune effector cell, wherein the cell is autologous or allogeneic (page 30, [0022]). The SIRs can also be expressed in induced pluripotent stem cells (iPSC), that can give rise to immune effector cells (page 49, [0057]).
WO’795 further teaches that the cell is a T cell and the T cell is deficient in one or more of endogenous T cell receptor trains. T cells stably lacking expression of functional TCR according to the disclosure may be produced using a variety of approaches including ZFN, CRISPR, and shRNA targeting of the endogenous T cell genes (page 224, [00353]).
WO’795 further teaches the use of expression cassettes and teaches that the functional units of the SIR can be inserted into a genomic locus, for example, at the TCRα constant chain (TRAC) locus and expressed as a single polynucleotides. WO’795 also teaches that the functional units can be inserted in the TCR chain beta1 (TRBC1) locus (page 268, [00487]-[00488]); page 47, [0056]). WO’795 also teaches that the SIRs can be expressed so that they are under the control of an endogenous promoter, e.g., TCRα or TCRβ promoter (page 49, [0057]).
WO’795 further teaches a method of making a SIR expressing immune effector cell, comprising introducing at least one vector or at least one polynucleotide into an immune effector cell or a hematopoietic stem cell or progenitor cell that can give rise to an immune effector cell under conditions such that the SIR polypeptide is expressed (page 388, claim 170).
WO’795 further teaches a method of providing anti-disease immunity in a subject comprising administering to the subject an effective amount of the immune effector cell or a stem cell that can give rise to an immune effector cell, wherein the cell is an autologous T cell or an allogeneic T cell, or an autologous NKT cell or an allogeneic NKT cell or an autologous or an allogeneic hematopoietic stem cell or an autologous or an allogeneic iPSC that can give rise to an immune effector cell (page 389, claim 176).
WO’795 also teaches a method of treating or preventing a disease associated with the expression of a disease associated antigen in a subject, comprising administering to the subject an effective amount of an immune effector cell comprising a SIR molecule, where the SIR molecule comprises one or more of T-cell receptor constant chains joined via an optional linker to one or more of antigen binding domains that bind to disease-associated antigens, where the disease associated antigen is selected from a group consisting of antigens that overlap with those of instant claim 39 (pages 395-398, claim 180). WO’795 further teach that the disease associated with the expression of the disease associated antigen is selected from the group consisting of a proliferative disease, a precancerous condition, a cancer, and a non-cancer related indication associated with expression of the disease-associated antigen.
While WO’795 does not explicitly disclose that the constructs in Fig 5A-Q comprise the optional linker between the VHH domains and the TCR constant chains, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to include an Ig linker domain, such as IgCL, IgG1-CH1, IgG2-0C CH1, IgG2-IC CH1, IgG3 CH1, IgG4 CH1, IgAI CH1, IgA2 CH1, IgD CH1, IgE CH1, IgE CH1, and IgM CH1 linker domains, based on the teachings of WO’795 as a whole. It would have been obvious to include the Ig linker domain as WO’795 teaches its optional inclusion in the SIR constructs between the one or more non-natural TCR antigen binding domains and the TCR constant chains. Thus, an ordinarily skilled artisan would have had a reasonable expectation of success.
Regarding claim 3, claims 1 and 2 are rendered obvious by WO’795 which teaches a second module comprising an Ig linker domain, which is presented in the instant claims as an alternative to a vH, Va, Vg, vL, Vb, or Vd. None of claims 1-3 require that the second module comprise a vH, Va, Vg, vL, Vb, or Vd. Therefore, the alternative teaching of an Ig linker domain by WO’795 renders obvious claim 3.
Regarding claims 4 and 5, as discussed above, WO’795 teaches Ig linker domains in table 6D. The linkers disclosed overlap with the Ig linker domains of the instantly claimed invention. For instance, WO’795 teaches that the linker can be IgG1-CH1, which has a protein sequence of SEQ ID NO: 2993. WO’795, SEQ ID NO: 2993 is identical to instant SEQ ID NO: 11833, as shown in the alignment below.
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Additionally, the Ig linker domain is a fully human Ig linker domain.
Regarding claim 6, WO’795 further teaches that a linker can be used to join two or more domains or regions of an SIR and can be anywhere from 1 to 500 amino acids in lengths and be cleavable or non-cleavable. Said non-cleavable linkers may be composed of flexible residues which allow freedom of motion of adjacent protein domains relative to each other. Non-limiting examples of such residues include glycine and serine (page 70, [00121]). WO’795 teaches linkers including (G4S)x3, (G3S)n where n is 1-10 (page 70, [00122]), which meet the limitations of the linkers being instant SEQ ID NOs: 11714, 11718, and 11716. WO’795 also teaches linkers including MYC Tag, V5 Tag, AcV5 Tag, Streptag II, FLAG tag, or HA (pages 70-71, [00121]). WO’795 provides additional linkers in Table 6D, including HIS-TAG, AVI-TAG, and G4Sx2-Tag (page 139).
Regarding claims 8-12 WO’795 teaches that the SIRs encode one or more T cell receptor constant chains or regions. The nucleic acid sequences of exemplary T cell receptor constant chains or regions that can be used to make a SIR are provided in Table 4.
Table 4 includes a domain that comprises CD3zECDTMCP-opt2, having a PRT of SEQ ID NO: 3021, which comprises instant SEQ ID NO: 11906, as recited in claim 8, as shown in the alignment below:
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The CD3zECDTMCP-opt2 of WO’795, SEQ ID NO: 3021, also comprises instant SEQ ID NO: 11875, as recited in instant claim 10; instant SEQ ID NO: 11881, as recited in instant claim 11; as well as instant SEQ ID NO: 11886, as recited in instant claim 12, as shown in the alignments below, respectively:
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Table 4 also includes h-TCR-alpha-constant-region_X02883.1, having a PRT of SEQ ID NO: 3010. US’795, SEQ ID NO: 3010 is identical to instant SEQ ID NO: 11732, as recited in instant claim 9, as shown in the alignment below:
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WO’795 also teaches that the constant region is hTCRb-S57C-opt (also hTCRb-S57C-opt1), having a PRT of SEQ ID NO: 3027. WO’795, SEQ ID NO: 3027 is identical to instant SEQ ID NO: 11749, as recited in instant claim 9, as shown in the alignment below:
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WO’795 teaches that a SIR with a Thr48C mutation in Cα and a S57C mutation in Cβ1 or Cβ2 chain results in an additional disulfide bond between the two TCR constant chains. This, in turn, results in reducing mispairing with endogenous TCR chains in an immune cell and enhanced functionality (page 62, [0090]).
Regarding claim 17, WO’795 teaches that VHH domains that target CD20, including a VHH with a protein sequence of SEQ ID NO: 12289. WO’795, SEQ ID NO: 12289, is identical to instantly claimed SEQ ID NO: 11589, as shown in the alignment below:
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Claims 29-31 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2018/102795 A2 (Chaudhary, P.M.) 07 June 2018 as applied to claims 1, 22, and 26-27 above, and in further view of Eyquem, J., et al (2017) Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection Nature 543; 113-117 and Extended Data.
WO’795 teaches the cell or population of cells of claims 26 and 27 as discussed in detail above.
As discussed above, WO’795 teaches that the T cells are deficient in one or more endogenous T cell receptors and can be made so using approaches including CRISPR targeting the endogenous T cell genes (page 224, [00353]). WO’795 also teaches that the SIR can be inserted into a genomic locus, for example TRAC or TRBC1 (page 268, [00487]-[00488]); page 47, [0056]).
WO’795, however, does not teach that the placement of the SAR disrupts or abolishes the endogenous expression of a TCR as claimed or that it results in enhanced expression and/or activity of the non-naturally occurring immune receptor compared to its expression and/or activity with wild-type endogenous TCR.
Eyquem teaches that CARs are synthetic receptors that redirect and reprogram T cells to mediate tumour rejection. CARs are typically transduced into the T cells of a patient using γ retroviral vectors or other randomly integrating vectors, which may result in clonal expansion, oncogenic transformation, variegated transgene expression and transcriptional silencing. Recent advances in genome editing enable efficient sequence specific interventions in human cells, including targeted gene delivery to the CCR5 and AAVS1 loci. Eyquem demonstrates that directing a CD19 specific CAR to the T-cell receptor α constant (TRAC) locus, not only results in uniform CAR expression in human peripheral blood T cells, but also enhances T cell potency, with edited cells vastly outperforming conventionally generated CAR T cells in a mouse model of ALL. It is further demonstrated that targeting the CAR to the TRAC locus averts tonic CAR signaling and establishes effective internalization and re-expression of the CAR following single or repeated exposure to antigen, delaying effector T cell differentiation and exhaustion (abstract). To disrupt the TRAC locus and place the CD19 specific CAR under its transcriptional control, Eyquem used a gRNA targeting the 4’ end of the first exon of TRAC and an adeno-associated virus vector repair matrix encoding a self-cleaving P2A peptide followed by the CAR cDNA. T cell electroporation of Cas9 mRNA and gRNA yielded a high knockout frequency with limited cell death (page 113, right column, paragraph 1).
Eyquem teaches that targeting a CAR coding sequence to the TCR locus, placing it under the control of endogenous regulatory elements, reduces tonic signaling, averts accelerated T-cell differentiation and exhaustion, and increase the therapeutic potency of the T cells (paragraph bridging pages 116-117).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the cells or population of cells disclosed by WO’795 by integrating the SIR into the TRAC locus thereby disrupting the endogenous TCR using the methods disclosed by Eyquem. Additionally, an ordinarily skilled artisan would have reasonable expected that the methods would result in cells that have enhanced expression and activity compared to those with wild-type endogenous TCR based on the teachings of Eyquem. An ordinarily skilled artisan would have been motivated to use the methods of Eyquem for integrating the SIR in the TRAC locus in order to achieve benefits such as reducing tonic signaling, averting accelerated T cell differentiation and exhaustion, increasing therapeutic potency, and establishing effective internalization and re-expression of the SAR following antigen exposure. An ordinarily skilled artisan would have had a reasonable expectation of success as the SIR disclosed by WO’795 is a synthetic immune receptor similar to a CAR that is integrated into a T cell. Additionally, WO’795 teaches that the SIR can be inserted into the TRAC locus of the T cell and that the endogenous TCR can be interrupted.
While the teachings of Eqyuem provide a reasonable expectation that expression and activity would be enhanced compared to those with wild type endogenous TCRs, these properties are also mechanistic outcomes that would flow naturally from following the suggestions of the prior art and cannot be the basis for patentability when the differences would have otherwise been obvious.
MPEP 2145 II. states “The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious.” The MPEP section further states “The recitation of an additional advantage associated with doing what the prior art suggests does not lend patentability to an otherwise unpatentable invention.”
Claim 36 is rejected under 35 U.S.C. 103 as being unpatentable over WO 2018/102795 A2 (Chaudhary, P.M.) 07 June 2018 in view of WO 2019/217512 A1 (Zynda, E., et al) 14 Nov 2019 as evidenced by Pavlacky, J. and J. Polak (2020) Technical feasibility and physiological relevance of hypoxic cell culture models Frontiers in Endocrinology 11(57); 1-15.
The teachings of WO’795 are as discussed in detail above. Ad discussed above, WO’795 teaches the cell or population of cells of claim 22.
WO’795 further teaches the expansion of the SIR- and/or CAR- and/or Ab-TCR- and/or TRUC and/or cTCR expressing immune effector cells. WO’795 also teaches the use of XVIVO media in expansion (page 226, [00357]; page 278, [00512]).
WO’795, however, does not disclose that the cells are expanded in a gas permeable flask under normoxic or hypoxic conditions.
WO’512 teaches improvements in mammalian cell culture. In particular, compositions, methods, and kits for culturing and expanding mammalian cells, e.g., immune cells such as T cells and NK cells. In some aspects, compositions and methods are provided for enhancing the proliferation of cells in serum free media (abstract).
WO’512 teaches that some aspects of the methods provided relate to access of cell being cultured to oxygen and the removal of carbon dioxide. It is generally desirable for these cells to have ready access to oxygen with the efficient removal of carbon dioxide. Along these lines, typically culture is performed in an incubator with O2 concentrations between 15-25% and CO2 concentrations between 2-7%. WO’512 teaches the use of a gas permeable membrane in contact with the culture media. Such membranes may be located at the bottom of a culture vessel and allow for both O2 to enter the culture media and for CO2 to leave the culture media. WO’512 teaches the use of G-REX ® culture vessels, which incorporate gas permeable membranes (page 3, [0013]-[0015]). WO’512 also teaches the use of X-VIVO media (page 6, [0029]). The O2 conditions disclosed by WO’512 meet the limitation of normoxic conditions as evidenced by Pavlacky, which teaches 18.6% O2 in an incubator is what many would consider as a conventional, standard, or “normoxic” setup (page 3, left column, paragraph 1).
WO’512 further teaches that the methods disclosed can be used to expand CAR T cells prior to administration to a patient (pages 26-27, [0132]).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the cell/cell population disclosed by WO’795 by expanding the SAR expressing cells in a gas permeable flask under normoxic conditions as disclosed by WO’512. An ordinarily skilled artisan would have been motivated to expand the cells under the conditions disclosed by WO’152 in order to enhance proliferation of the cells. An ordinarily skilled artisan would have had a reasonable expectation of success as WO’512 teaches that the methods can be used to expand cells comprising synthetic immune receptors, such as CARs, and also teaches the use of X-VIVO media, which is also taught by WO’795.
Claim 37 is rejected under 35 U.S.C. 103 as being unpatentable over WO 2018/102795 A2 (Chaudhary, P.M.) 07 June 2018 and WO 2019/217512 A1 (Zynda, E., et al) 14 Nov 2019 as applied to claim 36 above, and in further view of Dougan, M., et al (2010) IAP inhibitors enhance co-stimulation to promote tumor immunity J. Exp. Med. 207(10); 2195-2206.
The combination of WO’795 and WO’512 teach the method of claim 36 as discussed in detail above.
The combination of WO’795 and WO’512, however, do not disclose the inclusion of a SMAC mimetic or a NIK agonist compound.
Dougan teaches that inhibitor of apoptosis proteins (IAPs) have been shown to modulate nuclear factor kB (NF-kB) signaling downstream of TNF family receptors, positioning them as essential survival factors in several cancer cell lines. In addition to roles in cancer, increasing evidence suggests that IAPs have an important function in immunity; however, the impact of IAP antagonists on antitumor immune responses is unknown. Dougan examined the consequences of IAP antagonism on T cell function in vitro and in the context of a tumor vaccine in vivo. It was found that IAP antagonists can augment human and mouse T cell responses to physiologically relevant stimuli. The activity of IAP antagonists depends on the activation of NF-kB2 signaling, a mechanism paralleling that responsible for the cytotoxic activity in cancer cells. It is further shown that IAP antagonists can augment both prophylactic and therapeutic antitumor vaccines in vivo. Dougan teaches that the findings disclosed indicate an important role for the IAPs in regulating T-cell dependent responses and suggest that targeting IAPs using small molecule antagonists may be a strategy for developing novel immunomodulating therapies against cancer (abstract).
Dougan teaches that IAPs are regulated endogenously by second mitochondrial derived activator of caspase (SMAC), which interacts with IAP baculovirus inhibitory repeat domains. Several pharmacologic SMAC mimetics have been developed that induce tumor death by binding to the RING domain containing IAPs leading to ubiquitin mediated destruction (pages 2195-2196, paragraph bridging pages). Dougan teaches that IAP agonists have co-stimulatory activity in effector cells. In the study, Dougan exposed CD4+ T cells to several IAP antagonists, including M1/LBW-242, M2, and M3, to a control compound having a similar structure (page 2196, right column, paragraph 3). It is noted that, at least LBW-242, is a SMAC mimetic. Dougan teaches that the IAP antagonists had a significant effect on T cell function, leading to a substantial increase in T cell numbers after 72 hours of culture. In addition to enhanced proliferation, T cells stimulated in the presence of IAP antagonists showed other signs of enhanced activation (page 2196, right column, paragraphs 4-5).
Dougan teaches that, collectively, the findings establish IAPs as important regulators of T cell activation and define IAP antagonists as a novel class of immunomodulating agents. Unlike conventional adjuvants, IAP antagonists act in a co-stimulatory capacity, enhancing response to physiological immune signals in both mice and humans, while lacking intrinsic stimulatory capacity. The co-stimulatory effect is striking in T cells where IAP antagonism in the context of stimulation leads to enhanced cytokine secretion, as well as increased proliferation an expression of activation markers. IAP antagonism appears to co-stimulate T cells by blocking the ability of cIAPs to inhibit alternative NF-kB signaling, likely through their ability to regulate NIK (page 2203, right column, paragraphs 3-4).
Dougan further teaches that, in mice it was shown that in vivo administration of IAP antagonists can augment the efficacy of tumor vaccines. IAP antagonist treatment is associated with systemic hyperresponsive T cells in the absence of overt autoimmunity. It has been demonstrated that inhibiting IAPs removes a physiological signaling brake, allowing for enhanced responses from both CD4+ and CD8+ T cells as well as other key antitumor effector cells, including NKT cells and NK cells (page 2204, left column, paragraph 3).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method taught by the combination of WO’795 and WO’512 by further including an IAP antagonist, such as a SMAC mimetic, in the culture. An ordinarily skilled artisan would have been motivated to further include a SMAC mimetic in order to enhance proliferation and activation of the T cells while removing a physiological signaling break allowing for enhanced responses and hyperresponsive T cells. An ordinarily skilled artisan would have had a reasonable expectation of success as Dougan studied the impact of SMAC mimetics on T cells, which is the same type of cells taught by both WO’795 and WO’512.
Claims 1-28, 35, and 38-40 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2018/102795 A2 (Chaudhary, P.M.) 07 June 2018 and WO 2018/148454 A1 (O’Donoghue, G.P., et al) 16 Aug 2018.
The instant claims are rejected above as being obvious over WO’795. The claims are further rejected here to demonstrate that a SAR in which the first module is the AABD and the second is a vL and vH would have been obvious. Specifically, where the SAR comprises a first polypeptide chain comprising a VHH linked to a vH and the second polypeptide chain comprises a vL. It is noted that this is the general structure of the SAR that was elected by applicant.
The teachings of WO’795 are as discussed above.
As discussed above, WO’795 teaches that the SAR comprises one or more non-natural TCR antigen binding domains and teaches that the domains can include binding elements including vH and vL domains as well as scFv, and vHH (pages 349-350, claim 1).
WO’795 also teaches constructs including Fig. 3A-Q, in which vH and vL are connected to TCR constant chains. WO’795 also teaches constructs that comprise a vH, vL, and vHH as shown in Fig. 6A-Q. For convenience and clarity, Fig. 3A and Fig. 6B are shown below as examples:
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As demonstrated in Fig. 3A, WO’795 considered synthetic receptors in which a VH was linked to the TCR alpha constant chain and a VL was linked to the TCR beta constant chain.
The constructs depicted in WO’795, however, differ from the instantly claimed constructs in that, when all of a vH, vL, and vHH are used in combination, WO’795 depicts the vH/vL on one receptor chain (in Fig. 5B the “first polypeptide chain”) and the vHH on the other (in Fig. 5B the “second polypeptide chain”). WO’795, does not explicitly that the first chain comprises a VHH attached to a vH while the second chain comprises a vL domain.
WO’454 teaches chimeric T cell antigen receptors (TCRs) comprising modified TCR chains. The modified TCR chains include fusion polypeptides having one or more heterologous antigen-binding domains fused to the extracellular domain of the TCR chain. Modified TCR chains also include chains that are modified in various other ways including cystine modification, domain swapping, and combinations thereof. Also provided are nucleic acids encoding the modified TCR chains as well as nucleic acids encoding chimeric TCRs and recombinant expression vectors comprising such nucleic acids. Immune cells that are genetically modified or otherwise include the described chimeric TCRs, recombinant expression vectors encoding chimeric TCRs, and/or the described nucleic acids are also provided. Methods are provided, such as methods of killing a target cell and/or treating a subject for a condition, e.g., through the use of the chimeric TCRs, nucleic acids, expression vectors, and/or immune cells (abstract).
WO’454 teaches a nucleic acid encoding a chimeric TCR comprising a modified α-chain and a modified β-chain that, when present in an immune cell membrane, activates the immune cell when the chimeric TCR binds an antigen, wherein: a) the modified α-chain is a fusion polypeptide comprising a heterologous antigen binding domain that specifically binds the antigen, fused to the extracellular domain of a TCR α-chain; or b) the modified β-chain is a fusion polypeptide comprising a heterologous antigen-binding domain that specifically binds the antigen fused to the extracellular domain of a TCR β-chain (page 104, claim 1). WO’454 further teaches that the antigen binding domain can be an antibody and an scFv or a single domain antibody (page 104, claims 5-6). WO’454 alternatively teaches that the antigen binding domain including a ligand binding domain of a receptor (page 104, claim 7). WO’454 teaches that the antigen binding domain can be fused directly to the extracellular domain or connected by a linker (pages 104-105, claims 8-9). WO’454 further teaches that the chimeric TCR comprises a recombinant disulfide bond between an α-chain cysteine mutation and a β-chain cysteine mutation and that the mutations can be T48C (α-chain) and S57C (β-chain) (pages 105-106, claims 19-20). WO’454 further teaches that the chains comprise connecting, transmembrane, and cytoplasmic regions (page 106, claims 22-24). WO’454 further teaches embodiments in which the α-chain is a fusion polypeptide comprising two or more heterologous antigen-binding domains, that specifically bind a different antigen fused to the extracellular domain of a TCR α-chain or a TCR β-chain, where the polypeptide comprises a first heterologous antigen-binding domain fused to the extracellular domain of a TCR α-chain or a TCR β-chain and a second heterologous binding domain fused to the first heterologous antigen-binding domain (page 106, claims 25-28).
For instance, WO’454 teaches the following constructs in Figs. 17 and 18:
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It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the bispecific SIRs (for instance the construct shown in Fig. 6B) disclosed by WO’795 by alternatively attaching the VHH domain to the vH or vL domain (for instance the construct in Fig. 3A) based on the teachings of WO’454. It would have been obvious to construct the SIR by attaching the VHH domain to the vH or vL domain as WO’454 teaches the attachment of a heterologous antigen binding domain, such as a single domain antibody, to the extracellular domain of the TCR α-chain or a TCR β-chain. An ordinarily skilled artisan would have had a reasonable expectation of success as both WO’795 and WO’454 are drawn to chimeric receptors. Additionally, both references teach heterodimeric receptors and both teach, for instance, a T48C and S57C mutation in the TCR constant regions to form a disulfide bond between the TCR α-chain and TCR β-chain.
Alternatively, it would have been obvious to substitute the TCR α-chain or a TCR β-chain variable domains (αV and βV) in the construct disclosed by WO’454 with antibody vH and vL domains based on the teachings of WO’795. It would have been obvious to make this substitution as WO’795 teaches synthetic immune receptors in which one or more non-natural TCR antigen binding domains, including an antibody vH and vL domain, is attached to TCR constant chains to form a chimeric TCR. An ordinarily skilled artisan would have had a reasonable expectation of success because both WO’454 and WO’795 are drawn to chimeric receptors.
Regarding claim 17, WO’795 further teaches that the vH and vL can be from the anti-CD19 antibody hu-mROO5-1, which has a vH of SEQ ID NO: 12185 and a vL of SEQ ID NO: 12067 (page 117, top row; page 127, bottom row). WO’795, SEQ ID NOs: 12185 and 12067 are identical to instant SEQ ID NOs: 11081 and 10839, respectively, as shown in the alignment below:
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Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
US 12,269,859 B2
Claims 1-28, 35, and 38-41 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-23 of U.S. Patent No. 12,269,859 in view of WO 2018/102795 A2 (Chaudhary, P.M.) 07 June 2018 and WO 2018/148454 A1 (O’Donoghue, G.P., et al) 16 Aug 2018.
US’859 claims at least one recombinant polynucleotide encoding a synthetic immune receptor, wherein the SIR comprises a heterodimer of two T-cell receptor (TCR) constant chains selected from those recited in the claim, part a; and an optional linker; and one or more non-natural TCR antigen binding domain(s) linked to (a) selected from a group which includes a vH, vL, scFv, SDAB, camelid VHH, monomeric variable region of an antibody, a non-immunoglobulin antigen binding scaffold selected from the group consisting of a DARPIN, an antibody, an affilin, an adnectin, an affitin, an obody, a repebody, a fynomer, an alphabody, an avimer, an atrimer, a centryin, a pronectin, an anticalin, a kunitz domain, an Armadillo repeat protein, and function fragments thereof; a receptor or a fragment thereof; a ligand or a fragment thereof; and an autoantigen or a fragment thereof.
The claims further claims that the non-natural TCR antigen binding domain binds to an antigen selected from a group consisting of antigens that overlap with those of the instant claims. US’859 further claims that the antigen binding domain bins CD19 and comprises a polypeptide selected from a group which includes SEQ ID NOs: 12185 and 12067, which are identical to instant SEQ ID NOs: 11081 and 10839, respectively.
US’859 further claims at least one vector comprising the at least one recombinant polynucleotide, where the vector is selected from the group consisting of a DNA vector, an RNA vector, a plasmid, a lentivirus vector, an adenoviral vector, a retrovirus vector, a baculovirus vector, a sleeping beauty transposon vector, and a piggyback transposon vector. US’859 further claims a recombinant immune effector cell or stem cell that can differentiate into an immune effector cell comprising at least one of the SIR polynucleotides. US’859 claims that the immune cells include T cells, NK cells, and others, and are autologous or allogeneic.
US’859 claims that the SIR comprises a heterodimer of two T-cell receptor constant chains with mutations in 48C and 57C.
The claims of US’859 differ from the instantly claimed invention in that the claims of US’859 do not disclose that the first module of the receptor is an AABD and the second module is vL, vH, Va, Vb1, Vb2, Vg, Vd, scFv, scTCR, Ig linker domain, or a combination thereof. Additionally, US’859 does not claim a method of providing anti-disease immunity or a method of treating or preventing a disease by administering an immune cell expressing a SAR.
The teachings of WO’795 and WO’454 are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the claims of US’859 by using an Ig linker domain in the second module as disclosed by WO’795, and to use the SAR in the methods disclosed by WO’795. It would have been obvious to use an Ig linker domain as the linker in the second module as WO’795 teaches structures that overlap with those of the claims of US’859 and teaches that the linker can be an Ig linker domain. It would have been obvious to use the SAR in the methods disclosed by WO’795 as WO’795 teaches the use of similarly structured synthetic receptors for use in such methods. Thus, an ordinarily skilled artisan would have had a reasonable expectation of success.
Alternatively, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the claims of US’859 by alternatively attaching the VHH domain to a vH or vL domain which are connected to TCR constant regions based on the teachings of WO’454. It would have been obvious to construct the SIR by attaching the VHH domain to the vH or vL domain as WO’454 teaches the attachment of a heterologous antigen binding domain, such as a single domain antibody, to the extracellular domain of the TCR α-chain or a TCR β-chain. An ordinarily skilled artisan would have had a reasonable expectation of success as both US’859 and WO’454 are drawn to chimeric receptors. Additionally, both references teach heterodimeric receptors and both teach, for instance, a T48C and S57C mutation in the TCR constant regions to form a disulfide bond between the TCR α-chain and TCR β-chain.
Regarding claim 41, US’859 claims that the recombinant polynucleotide encodes a polypeptide with a sequence including SEQ ID NO: 13202. While US’859 does not claim the polynucleotide that encodes this polypeptide, WO’795 teaches the same sequence and teaches that the sequence is encoded by SEQ ID NO: 11245, which is identical to instant SEQ ID NO: 7347.
It would have been prima facie obvious to one of ordinary skill in the art to modify the claims of US’859 to include a polynucleotide of SEQ ID NO: 7347 based on the teachings of WO’795. It would have been obvious to make this inclusion as the polynucleotide was recognized in the prior art as encoding the claimed polypeptide.
Claims 29-31 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-23 of U.S. Patent No. 12,269,859 in view of WO 2018/102795 A2 (Chaudhary, P.M.) 07 June 2018 and WO 2018/148454 A1 (O’Donoghue, G.P., et al) 16 Aug 2018 as discussed above, and in further view of Eyquem, J., et al (2017) Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection Nature 543; 113-117 and Supplementary information.
The claims of US’859 modified by WO’795 and WO’454 teach the cells or population of cells of instant claims 26 and 27 as discussed in detail above.
The combination, however, does not teach that the placement of the SAR disrupts or abolishes the endogenous expression of a TCR as claimed or that it results in enhanced expression and/or activity of the non-naturally occurring immune receptor compared to its expression and/or activity with wild-type endogenous TCR.
The teachings of Eyquem are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the cells or population of cells disclosed by the combination of US’859 modified by WO’795 and WO’454 by integrating the SIR into the TRAC locus thereby disrupting the endogenous TCR using the methods disclosed by Eyquem. Additionally, an ordinarily skilled artisan would have reasonable expected that the methods would result in cells that have enhanced expression and activity compared to those with wild-type endogenous TCR. An ordinarily skilled artisan would have been motivated to use the methods of Eyquem for integrating the SIR in the TRAC locus in order to achieve benefits such as reducing tonic signaling, averting accelerated T cell differentiation and exhaustion, increasing therapeutic potency, and establishing effective internalization and re-expression of the SAR following antigen exposure. An ordinarily skilled artisan would have had a reasonable expectation of success as the SIR disclosed by WO’795 is a synthetic immune receptor similar to a CAR that is integrated into a T cell. Additionally, WO’795 teaches that the SIR can be inserted into the TRAC locus of the T cell and that the endogenous TCR can be interrupted.
Claims 36 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-23 of U.S. Patent No. 12,269,859 in view of WO 2018/102795 A2 (Chaudhary, P.M.) 07 June 2018 and WO 2018/148454 A1 (O’Donoghue, G.P., et al) 16 Aug 2018 as discussed above, and in further view of WO 2019/217512 A1 (Zynda, E., et al) 14 Nov 2019 as evidenced by Pavlacky, J. and J. Polak (2020) Technical feasibility and physiological relevance of hypoxic cell culture models Frontiers in Endocrinology 11(57); 1-15.
The claims of US’859 modified by WO’795 and WO’454 teach the cells or population of cells of instant claim 22 as discussed in detail above.
The combination, however, does not disclose that the cells are expanded in a gas permeable flask under normoxic or hypoxic conditions.
The teachings of WO’512 are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the cell/cell population disclosed by the combination of US’859 modified by WO’795 and WO’454 by expanding the SAR expressing cells in a gas permeable flask under normoxic conditions as disclosed by WO’512. An ordinarily skilled artisan would have been motivated to expand the cells under the conditions disclosed by WO’152 in order to enhance proliferation of the cells. An ordinarily skilled artisan would have had a reasonable expectation of success as WO’512 teaches that the methods can be used to expand cells comprising synthetic immune receptors, such as CARs, and also teaches the use of X-VIVO media, which is also taught by WO’795.
Claims 37 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-23 of U.S. Patent No. 12,269,859 in view of WO 2018/102795 A2 (Chaudhary, P.M.) 07 June 2018, WO 2018/148454 A1 (O’Donoghue, G.P., et al) 16 Aug 2018, and WO 2019/217512 A1 (Zynda, E., et al) 14 Nov 2019 as discussed above, and in further view of Dougan, M., et al (2010) IAP inhibitors enhance co-stimulation to promote tumor immunity J. Exp. Med. 207(10); 2195-2206.
The claims of US’859 modified by WO’795, WO’454, and WO’512 teach the method of claim 36 as discussed in detail above.
The combination, however, does not disclose the inclusion of a SMAC mimetic or a NIK agonist compound.
The teachings of Dougan are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method taught by the combination of US’859 modified by WO’795, WO’454, and WO’512 by further including an IAP antagonist, such as a SMAC mimetic, in the culture. An ordinarily skilled artisan would have been motivated to further include a SMAC mimetic in order to enhance proliferation and activation of the T cells while removing a physiological signaling break allowing for enhanced responses and hyperresponsive T cells. An ordinarily skilled artisan would have had a reasonable expectation of success as Dougan studied the impact of SMAC mimetics on T cells, which is the same type of cells taught by both US’859, WO’795, WO’454, and WO’512.
18/275,957
Claim 1-28, 35, and 38-41 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 44-45, 52, 54-56, 58, 63-64, 68, 71-72, 93, 118, 127, 137, 148, and 246 of copending Application No. 18/275,957 in view of WO 2018/102795 A2 (Chaudhary, P.M.) 07 June 2018 and WO 2018/148454 A1 (O’Donoghue, G.P., et al) 16 Aug 2018.
App’957 claims an at least one recombinant polynucleotide encoding a synthetic SAR that speicifcally binds to a target antigen, wherein the SAR comprises a dimer of two polypeptide chains comprising: 1. A first module comprising one or more heterologous binding domains selected from a group consisting of an antibody, antibody fragment vH, vL, scFv, SDAB, vHH, SVH, SVL, a non-immunoglobulin antigen binding scaffold, DARPIN, affibody, affilis, adnectin, affitin, obody, repebody, fynomer, alphabody, avimer, atrimer, centyrin, pronecti, anticalins, kunitz domain, an Armadillo repeat protein, D domain, and a fragment of any of the foregoing, a ligand binding domain of a receptor, a receptor binding domain of a ligand, an autoantigen, an adaptor binding domain, an Fc binding domain, a TCR, Va, Vb, Vg or Vd fragment. App’957 further claims that, when present, a vH domain of an antibody is attached to one polypeptide chain and the complementary vL domain is attached to the other, where the vH and vL form a Fv-like antigen binding domain. Similar recitations are set forth for Va and Vb and Vg and Vd domains. App’957 claims a second module comprising a membrane associated module where the first and second modules are operationally linked to a first and second MAM to form a non-T cell receptor module that is capable of activating at least on signaling pathway and/or recruiting at least one signaling adapter. App’957 further claims an optional third module comprising one or more AABD operably linked via optional linkers to the N-terminus or near the N-terminus of the first module of one or both polypeptide chains.
App’957 claims that the first and second MAM comprise the transmembrane/membrane anchored domain, optional cytosolic domain, hinge, and extracellular domain of a non-T cell receptor and/or a signaling adaptor optionally selected from those recited in claim 58. App’957 further claims that the SAR binds one or more antigens selected from those recited in claim 71, which overlap with those of the instant claims.
App’957 also claims that the VHH comprises a sequence including SEQ ID NO: 10695, which is identical to instant SEQ ID NO: 11531.
App’957 further claims an effector cell or a stem cell comprising the at least one polynucleotide and one or more optional accessory molecules. App’957 claims that the immune cells is a T cell, or NK cell. App’957 claims a method of providing anti-disease immunity in a subject comprising administering to the subject an autologous or allogeneic T cell, NK cell, macrophage, granulocyte, dendritic cell, hematopoietic stem cell, or iPSC that can give rise to an effector cell, optionally, the disease is a cancer, viral disease, autoimmune disease, degenerative disease, or an infection.
The claims of App’957 differ from the instantly claimed invention in that App’957 in that App’957 does not explicitly claim that the MAM comprises an extracellular domain or that the MAM comprises the extracellular, transmembrane, and intracellular domains of a polypeptide selected from a T cell receptor.
The teachings of WO’795 and WO’454 are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the claims of App’957 by substituting the MAM in the claims of App’957 with TCR constant chains as disclosed by the combination of WO’795 and WO’454. It would have been obvious to make this substitution, and one of ordinary skill in the art would have had a reasonable expectation of success as all of App’957, WO’795 and WO’454 are drawn to synthetic receptors and WO’795 and WO’454 demonstrate the use of TCR constant domains in such receptors. Thus, an ordinarily skilled artisan would have had a reasonable expectation of success.
Claims 29-31 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 44-45, 52, 54-56, 58, 63-64, 68, 71-72, 93, 118, 127, 137, 148, and 246 of copending Application No. 18/275,957 in view of WO 2018/102795 A2 (Chaudhary, P.M.) 07 June 2018 and WO 2018/148454 A1 (O’Donoghue, G.P., et al) 16 Aug 2018 as discussed in detail above, and in further view of Eyquem, J., et al (2017) Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection Nature 543; 113-117 and Supplementary information.
The claims of App’957 modified by WO’795 and WO’454 teach the cells or population of cells of instant claims 26 and 27 as discussed in detail above.
The combination, however, does not teach that the placement of the SAR disrupts or abolishes the endogenous expression of a TCR as claimed or that it results in enhanced expression and/or activity of the non-naturally occurring immune receptor compared to its expression and/or activity with wild-type endogenous TCR.
The teachings of Eyquem are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the cells or population of cells disclosed by the combination of App’957 modified by WO’795 and WO’454 by integrating the SIR into the TRAC locus thereby disrupting the endogenous TCR using the methods disclosed by Eyquem. Additionally, an ordinarily skilled artisan would have reasonable expected that the methods would result in cells that have enhanced expression and activity compared to those with wild-type endogenous TCR. An ordinarily skilled artisan would have been motivated to use the methods of Eyquem for integrating the SIR in the TRAC locus in order to achieve benefits such as reducing tonic signaling, averting accelerated T cell differentiation and exhaustion, increasing therapeutic potency, and establishing effective internalization and re-expression of the SAR following antigen exposure. An ordinarily skilled artisan would have had a reasonable expectation of success as the SIR disclosed by WO’795 is a synthetic immune receptor similar to a CAR that is integrated into a T cell. Additionally, WO’795 teaches that the SIR can be inserted into the TRAC locus of the T cell and that the endogenous TCR can be interrupted.
Claim 36 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 44-45, 52, 54-56, 58, 63-64, 68, 71-72, 93, 118, 127, 137, 148, and 246 of copending Application No. 18/275,957 in view of WO 2018/102795 A2 (Chaudhary, P.M.) 07 June 2018 and WO 2018/148454 A1 (O’Donoghue, G.P., et al) 16 Aug 2018 as discussed in detail above, and in further view of WO 2019/217512 A1 (Zynda, E., et al) 14 Nov 2019 as evidenced by Pavlacky, J. and J. Polak (2020) Technical feasibility and physiological relevance of hypoxic cell culture models Frontiers in Endocrinology 11(57); 1-15.
The claims of App’957 modified by WO’795 and WO’454 teach the cells or population of cells of instant claim 22 as discussed in detail above.
The combination, however, does not disclose that the cells are expanded in a gas permeable flask under normoxic or hypoxic conditions.
The teachings of WO’512 are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the cell/cell population disclosed by the combination of App’957 modified by WO’795 and WO’454 by expanding the SAR expressing cells in a gas permeable flask under normoxic conditions as disclosed by WO’512. An ordinarily skilled artisan would have been motivated to expand the cells under the conditions disclosed by WO’152 in order to enhance proliferation of the cells. An ordinarily skilled artisan would have had a reasonable expectation of success as WO’512 teaches that the methods can be used to expand cells comprising synthetic immune receptors, such as CARs, and also teaches the use of X-VIVO media, which is also taught by WO’795.
Claim 37 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 44-45, 52, 54-56, 58, 63-64, 68, 71-72, 93, 118, 127, 137, 148, and 246 of copending Application No. 18/275,957 in view of WO 2018/102795 A2 (Chaudhary, P.M.) 07 June 2018, WO 2018/148454 A1 (O’Donoghue, G.P., et al) 16 Aug 2018, and WO 2019/217512 A1 (Zynda, E., et al) 14 Nov 2019 as discussed in detail above, and in further view of Dougan, M., et al (2010) IAP inhibitors enhance co-stimulation to promote tumor immunity J. Exp. Med. 207(10); 2195-2206.
The claims of App’957 modified by WO’795, WO’454, and WO’512 teach the method of claim 36 as discussed in detail above.
The combination, however, does not disclose the inclusion of a SMAC mimetic or a NIK agonist compound.
The teachings of Dougan are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method taught by the combination of App’957 modified by WO’795, WO’454, and WO’512 by further including an IAP antagonist, such as a SMAC mimetic, in the culture. An ordinarily skilled artisan would have been motivated to further include a SMAC mimetic in order to enhance proliferation and activation of the T cells while removing a physiological signaling break allowing for enhanced responses and hyperresponsive T cells. An ordinarily skilled artisan would have had a reasonable expectation of success as Dougan studied the impact of SMAC mimetics on T cells, which is the same type of cells taught by both App’957, WO’795, WO’454, and WO’512.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claims are allowed.
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/AUDREY L BUTTICE/Examiner, Art Unit 1647
/SCARLETT Y GOON/Supervisory Patent Examiner
Art Unit 1693