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 .
Applicant’s amendment, filed 1/24/2023, is acknowledged.
Claims 1-20 are currently pending.
Election/Restrictions
Applicants’ election with traverse of Group II, claim 11, directed to a method of killing a target cancer call in an individual comprising administration of a genetically modified cytotoxic immune cell, and the species of: 1) CDH6 and AXL; and 2) BTTS and a CAR, filed on 1/07/2026, is acknowledged.
The traversal is on the grounds that Applicant argues that it would not be unduly burdensome to perform a search on all of the claims together in the present application. However, for the reasons discussed in the Restriction/Election requirement mailed on 10/08/2025, the inventive groups lack Unity of Invention, and this argument has not been found to be persuasive.
The requirement is still deemed proper and is therefore made FINAL.
Claims 1-10 and 12-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected inventions.
Claim 11 is under examination as reading on a method of killing a target cancer cell in an individual comprising administration of a genetically modified cytotoxic immune cell comprising one polypeptide that binds to CDH6 and another that binds to AXL, and wherein the cancer cells express CDH6 and AXL, wherein one polypeptide is a BTTS and the other is a CAR.
Specification
The disclosure is objected to because of the following informalities:
The use of the terms: Lenti-X (¶[002233]-[002234]), Fugene (¶[00224]), Dynabeads (¶[00224]), and CellTrace (¶[00229]) , which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore, the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
The specification recites “it ws” in ¶[00248], which should most likely be amended to “it was” to resolve a minor typographical error.
Appropriate correction is required.
Claim Interpretation
Claim 11 is dependent on claim 1, which recites “polypeptides bind to a selected antigen double or triplet of Table 1”. Thus, claim 11 is interpreted to recite a method of killing a target cancer cell in an individual comprising administration of a genetically modified cytotoxic immune cell expressing two different polypeptides to have a selected antigen doublet or triplet of Table 1, which is currently the elected Species of a CDH6 and ACL doublet. Claim 11 is also interpreted to have the limitations of the elected species of one polypeptide comprising a BTTS and the other comprising a CAR.
The instant specification discloses the definition of “binding-triggered transcriptional switch (BTTS)” (¶[0090]): “[a]s used herein, a "binding-triggered transcriptional switch" (BTTS) generally refers to a synthetic modular polypeptide or system of interacting polypeptides having an extracellular domain that includes a first member of a specific binding pair that binds a binding partner (i.e., the second member of the specific binding pair; e.g., an antigen), a binding-transducer and an intracellular domain. Upon binding of the second member of the specific binding pair to the BTTS the binding signal is transduced to the intracellular domain such that the intracellular domain becomes activated and performs some function within the cell that it does not perform in the absence of the binding signal…” Thus, the term “BTTS” is directed to polypeptides that bind to a specific partner. Upon binding to its specific partner the polypeptide “switch” turns on into an activated state to induce transcriptional changes in the cytotoxic cell expressing it, which the instant specification discloses can be activating transcription of genes or repressing transcription of genes (¶[0097]).
The instant specification discloses different polypeptides that can act as a BTTS, such as MESA polypeptides (¶[00101]): “…BTTS's that may be employed in the subject methods include, but are not limited to modular extracellular sensor architecture (MESA) polypeptides. A MESA polypeptide comprises: a) a ligand binding domain; b) a transmembrane domain; c) a protease cleavage site; and d) a functional domain. The functional domain can be a transcription regulator (e.g., a transcription activator, a transcription repressor)”; vWF based BTTS (¶[00103]): “…BTTS's that may be employed in the subject methods include, but are not limited to von Willebrand Factor (vWF) cleavage domain-based BTTS's, such as but not limited to e.g., those containing an unmodified or modified vWF A2 domain. A subject vWF cleavage domain-based BTTS will generally include: an extracellular domain comprising a first member of a binding pair; a von Willebrand Factor (vWF) cleavage domain comprising a proteolytic cleavage site; a cleavable transmembrane domain and an intracellular domain…”; and SynNotch receptors ([00104]-[00105]): “…BTTS's that may be employed in the subject methods include, but are not limited to chimeric Notch receptor polypeptides…SynNotch polypeptides are generally proteolytically cleavable chimeric polypeptides that generally include: a) an extracellular domain comprising a specific binding member; b) a proteolytically cleavable Notch receptor polypeptide comprising one or more proteolytic cleavage sites; and c) an intracellular domain…”
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 11 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Factors to be considered in determining whether undue experimentation is required to practice the claimed invention are summarized In re Wands (858 F2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)). The factors most relevant to this rejection are the scope of the claim, the amount of direction or guidance provided, the lack of sufficient working examples, the unpredictability in the art and the amount of experimentation required to enable one of skill in the art to practice the claimed invention.
Breadth of claims and nature of invention:
Claim 11 recites a method of killing a target cancer cell in an individual comprising administration of modified cytotoxic immune cells engineered to produce two broad genera of polypeptides, one polypeptide comprising a CAR and the other a BTTS, with no recited structure and the function of “binds to a selected antigen doublet or triplet from Table 1”, wherein the cancer cell expresses the same antigen doublet or triplet. For the purposes of examination this doublet or triplet is currently held to the elected doublet species of Cadherin-6 and AXL. Given that either of the polypeptides can be a CAR or a BTTS, the claim encompasses a method of killing a target cancel cell in an individual comprising administration of a modified cytotoxic immune cell engineered to produce a large genus of CARs with no recited structure and the function of “binds to CDH6” and a large genus of BTTS polypeptides with no recite structure and the function of “binds to AXL”; AND a method of killing a target cancel cell in an individual comprising administration of a modified cytotoxic immune cell engineered to produce a large genus of CARs with no recited structure and the function of “binds to AXL” and a large genus of BTTS polypeptides with no recite structure and the function of “binds to CDH6”.
The specification discloses identification of novel antigen targets on different tumor cell types to increase the efficacy and target discrimination of treatments targeting the cancers (Summary).
Amount of direction and existence of working examples:
The instant specification discloses the identification of potential candidate antigens that are co-expressed with other antigens on the surface of different types of tumor cells via a large screen of gene expression datasets (¶[00207]): “[p]otential candidate antigens were defined as genes with known or predicted cell surface expression, restricting the search space to current clinical targets and genes coding for transmembrane proteins. More specifically, we assembled a set of 29 unique clinical antigens along with their indications that have shown promise in the literature or are targets in currently active CAR or TCR trials and mapped them to their corresponding genes…”
¶[00238]: “[c]lustering-based scores were calculated for the current clinically targeted antigens. These single antigen scores were compared with those obtained for antigen pairs in which two clinically targeted antigens (clinical antigens) are combined, a clinical antigen is paired with a novel putative surface antigen, or two novel surface antigens are paired. A spreadsheet listing the top 10 antigen pairs from each type of combination (e.g. clinical-clinical, clinical-novel, etc) per cancer type ranked by clustering based scores was produced.”
Table 1 and Figures 2-4 disclose potential antigen targets to be used in cancer treatments. Notably, Table 1 discloses combinations of potential antigen candidates that are either all expressed on a cancer cell type, or wherein one or more antigen targets are not expressed on the cancer cell type (see cropped Table 1 below, which the first entry is NOT Her2 and SPN expression on AML cells):
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Two examples of methods of killing cancer cells in vitro are disclosed (¶[00246]-[00249]). Both of these are methods of killing renal cell carcinoma cells. To increase target selectivity, immune cells were modified to express a chimeric synNotch receptor and a chimeric antigen receptor. The synNotch drives the expression of the CAR in the modified cell, leading to more precise targeting of the desired cancer cells. The first example of this is a specific species of anti-AXL synNotch driving expression of a specific species of an anti-CD70 CAR (¶[00247] and Fig. 4A): “AND gate T cells were engineered in which an a-AXL synNotch drives expression of a CD70 CAR. This AND circuit was found to cause the specific lysis of RCC cells, but not of Raji B cells (Fig. 4A). Thus, the combinatorial recognition of AXL AND CD70 improves upon the CD70 single target CAR, allowing discrimination between RCC cells and B cells.”. The second example of this method of killing target cells in vitro is with a modified immune cell engineered to express a specific species of an anti-CDH6 synNotch to drive expression of an anti-AXL CAR (¶[00248] and Fig. 4B): “[w]hen an AND-gate T cell was constructed with a-CDH6 synNotch driving expression of an a-AXL CAR, it ws (sic) found that specific lysis was only seen for the RCC cell line, and not the lung epithelial cell line.”
Thus, the instant specification only discloses one specific example of a method of killing a target cell with an anti-CDH6 synNotch with one antigen binding polypeptide structure with the function of “binds to CDH6”, and an anti-AXL CAR with one binding polypeptide structure with the function of “anti-AXL”. The amino acid sequences of the polypeptides define their structure.
Level of predictability, state of prior art, and quantity of experimentation needed:
The claim is directed to methods of treatment comprising modified cells comprising either a broad class of CARs with no recited structure and the function of “binds to CDH6” and a broad class of BTTS polypeptides with no recite structure and the function of “binds to AXL”; or cells comprising a broad class of CARs with no recited structure and the function of “binds to AXL” and a broad class of BTTS polypeptides with no recite structure and the function of “binds to CDH6”, all with no recited structure (i.e., polypeptide sequences of the antigen binding domains with these binding functions).
However, the specification did not give the skilled in the art enough information to choose candidate antigen binding structures from the vast number of options of millions of candidates, and therefore required scientists to engage in a great deal of experimentation and failure. “That is not enablement”—it is a “hunting license.”
The specification discloses one example of a method of killing a target cell in vitro comprising contacting the cells with modified immune cells engineered to express one specific polypeptide sequence with the function of “binds to CDH6” and one specific polypeptide sequence with the function of “binds to AXL”, which is the method disclosed in Fig. 4B and ¶[00248].
In Amgen Inc. et al. v. Sanofi et al., 598 U.S. 594, 2023 USPQ2d 602 (2023), the Supreme Court held that claims drawn to a genus of monoclonal antibodies, which were functionally claimed by their ability to bind to a specific protein, PCSK9, were invalid due to lack of enablement. The claims at issue were functional, in that they defined the genus by its function (the ability to bind to specific residues of PCSK9) as opposed to reciting a specific structure (the amino acid sequence of the antibodies in the genus). The Supreme Court concluded that the patents at issue failed to adequately enable the full scope of the genus of antibodies that performed the function of binding to specific amino acid residues on PCSK9 and blocking the binding of PCSK9 to a particular cholesterol receptor, LDLR. This decision reaffirmed the prior decision made by the Federal District Court in Amgen Inc. v. Sanofi, Aventisub LLC., 987 F.3d 1080 (Fed. Cir. 2021).
The Court clarified that the specification does not always need to "describe with particularity how to make and use every single embodiment within a claimed class." Id. at 610-11. However, "[i]f a patent claims an entire class of processes, machines, manufactures, or compositions of matter, the patent’s specification must enable a person skilled in the art to make and use the entire class….The more one claims, the more one must enable." Id.
The specification may require a reasonable amount of experimentation to make and use the invention and what is reasonable will depend on the nature of the invention and the underlying art. For example, "it may suffice to give an example (or a few examples) if the specification also discloses some general quality … running through the class that gives it a peculiar fitness for the particular purpose" and "disclosing that general quality may reliably enable a person skilled in the art to make and use all of what is claimed, not merely a subset." Id. at 611 (internal quotations omitted). However, the Supreme Court found that Amgen failed to enable all that it claimed, even if allowing for a reasonable degree of experimentation. Id. at 613; see also Baxalta Inc. v Genentech, Inc., 81 F.4th 1362, 1367, 2023 USPQ2d 1103 (Fed. Cir. 2023) ("[t]he facts of this case are more analogous to—and are, in fact, indistinguishable from—those in Amgen. We do not interpret Amgen to have disturbed our prior enablement case law, including Wands and its factors."). Moreover, "[w]e see no meaningful difference between Wands' ‘undue experimentation’ and Amgen's ‘[un]reasonable experimentation’ standards. Id. at footnote 4. See also Guidelines for Assessing Enablement in Utility Applications and Patents in View of the Supreme Court Decision in Amgen Inc. et al. v. Sanofi et al., 89 FR 1563 (January 10, 2024), which explains that regardless of the technology the Wands factors should be used when assessing enablement.
However, while the specification in Amgen identified 26 exemplary antibodies that performed the claimed function by their amino acid sequences, the claims at issue were directed to a class which included "a ‘vast’ number of additional antibodies" that Amgen had not described by their amino acid sequences. Id. at 613. The Court found that Amgen sought to monopolize an entire class by their function, even though that class was much broader than the 26 exemplary antibodies disclosed by their amino acid structure. Id. at 613.
In Amgen Inc. v. Sanofi, Aventisub LLC, 987 F.3d 1080 (Fed. Cir. 2021), which the Supreme Court affirmed, the Federal Circuit explicitly applied the Wands factors to assess whether the specification of Amgen’s patent provided sufficient enablement, for purposes of 35 U.S.C. 112(a), to make and use the full scope of the claimed invention. The court relied on evidence showing that the scope of the claims encompassed millions of antibodies and that it was necessary to screen each candidate antibody in order to determine whether it met the functional limitations of the claim. Id. at 1088. Consequently, the Federal Circuit concluded that there was a lack of enablement. See also the following cases across various technology areas: McRO, Inc. v. Bandai Namco Games Am. Inc., 959 F.3d 1091, 2020 USPQ2d 10550 (Fed. Cir. 2020); Wyeth & Cordis Corp. v. Abbott Laboratories, 720 F.3d 1380, 107 USPQ2d 1273 (Fed. Cir. 2013); Enzo Life Sciences, Inc. v. Roche Molecular Systems, Inc., 928 F.3d 1340 (Fed. Cir. 2019); and Idenix Pharmaceuticals LLC v. Gilead Sciences Inc., 941 F.3d 1149, 2019 USPQ2d 415844 (Fed. Cir. 2019).
Amgen attempted to claim an entire class of compounds by their function, namely antibodies that bind to the “sweet spot” of PCSK9 thereby inhibiting it from binding to LDL, while only describing 26 amino acid sequences in its specification. The two processes, the “roadmap” and “conservative substitution” did not save Amgen. According to the Court, these amounted to “little more than two research assignments” which forced scientists to conduct “painstaking experimentation” to see what worked. (citing Incandescent Lamp). The Court therefore held that Amgen’s specification did not enable the claims.
This case is akin to the issue in Amgen Inc. v. Sanofi, Aventisub LLC, in which the court relied on evidence showing that the scope of the claims encompassed millions of antibodies and that it was necessary to screen each candidate antibody in order to determine whether it met the functional limitations of the claim. Sanofi-Aventisub at 1088. Consequently, the Federal Circuit concluded that there was a lack of enablement. While the specification in Amgen identified 26 exemplary antibodies that performed the claimed function by their amino acid sequences, the claims at issue were directed to a class that included “a ‘vast' number of additional antibodies” that Amgen had not described by their amino acid sequences. Id. at 1256. The Supreme Court found that Amgen sought to monopolize an entire class of antibodies by their function, which was much broader than the 26 exemplary antibodies disclosed by their amino acid structure.
In the instant case, the claim is directed to a method of administration of modified immune cells engineered to express CARs with no recited structure and the function of “binds to CDH6” and a broad class of BTTS polypeptides with no recite structure and the function of “binds to AXL”; or administration of cells engineered to express a broad class of CARs with no recited structure and the function of “binds to AXL” and a broad class of BTTS polypeptides with no recite structure and the function of “binds to CDH6”, all with no recited structure. These genera of CARs and BTTs polypeptides include includes millions of billions of polypeptide structures with widely varying amino acid sequences with these recited functions. The specification only discloses one specific example of an antigen binding domain with the function of “binds to CDH6” and one specific example of an antigen binding domain with the function of “binds to AXL”.
The instant claim is directed to are directed to classes of polypeptides that include “a ‘vast’ number” of additional structures with defined amino acid sequences in which the instant specification fails to describe. It would be necessary to first generate and then screen each candidate CAR and/or BTTS polypeptide to determine whether it met the functional limitations of “binds to CDH6” and/or “binds to AXL”. The Federal Circuit concluded that there was a lack of enablement, which was affirmed by the Supreme Court in Amgen.
The instant specification does not disclose any common structural feature delineating which CAR and BTTS polypeptide structures, including these polypeptides with extracellular domains from antibodies, will have the functions of “binds to CDH6” and/or “binds to AXL”. The only structure-function relationship guidance the specification provides is to disclose one example each of a extracellular domain for a CAR and/or a BTTS with the function of “binds to CDH6” and “binds to AXL”, respectively.
The instant claims simply direct skilled artisans to engage in the same iterative, trial-and-error process the inventors followed to discover the antibody structures they elected to disclose and that “[u]nder Amgen, such random trial-and-error discovery, without more, constitutes unreasonable experimentation that falls outside the bounds required by § 112(a).” Id. at *8, *10.
The Supreme Court’s 2023 decision in Amgen v. Sanofi, which mainly involves the enablement requirement, states that “where a patentee purports to invent an entire genus, it must enable the entire genus”; “disclosing how to produce some antibodies that perform a specified function is not equivalent to disclosing how to produce all such antibodies – and it is the latter that petitioners claim as their invention”; S. Ct.
Additionally, in its recent decision in Baxalta Inc. v. Genentech, Inc., No. 2022-1461, 2023 WL 6135930 (Fed. Cir. Sept. 20, 2023) the Federal Circuit found the facts of this case to be "materially indistinguishable from those in Amgen." Baxalta, 2023 WL 6135930, at *4. According to the Federal Circuit, claim 1 covers "millions of potential candidate antibodies" (id.) that bind to Factor IX/IXa and increase the procoagulant activity of Factor IXa. The court, however, noted that the specification discloses the amino acid sequence of just 11 of those antibodies. And like the roadmap in the patents at issue in Amgen, "the '590 patent's roadmap simply directs skilled artisans to engage in the same iterative, trial-and-error process the inventors followed to discover the [11] antibodies they elected to disclose." (Id.) Missing from the specification, according to the Federal Circuit, was "'a quality common to every functional embodiment' ... that would allow a skilled artisan to predict which antibodies will perform the claimed functions" (id.; quoting Amgen Inc. v. Sanofi., 598 U.S. 594, 614 (2023)), such as a common structural or other feature that would allow the antibodies to perform the claimed functions, or an explanation as to why the 11 antibodies do so and others do not. (Baxalta, 2023 WL 6135930, at *4). And the Federal Circuit was not persuaded by Baxalta's argument that its disclosed hybridoma-and screening process "predictably and reliably generates new claimed antibodies every time it is performed" (id.), because "it is undisputed that to practice the full scope of the claimed invention, skilled artisans must make candidate antibodies and screen them to determine which ones perform the claimed functions." (Id.).
The specification does not reasonably provide enablement to make and use the invention of instant claim 11.
Reasonable correlation must exist between the scope of the claims and scope of the enablement set forth. In view on the quantity of experimentation necessary the limited working examples, the nature of the invention, the state of the prior art, the unpredictability of the art and the breadth of the claims, it would take undue trials and errors to practice the claimed invention.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 11 is indefinite in the recitation “selected antigen doublet or triplet of Table 1” because it fails to point out what is included or excluded by the claim language. Tables 1 is subject to changes via amendments even after allowance. Such amendments would change the scope of claim 11. According to MPEP § 2173.05(s):
Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table "is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience." Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993) (citations omitted).
Incorporation by reference to Tables, Figures, and Examples as in this case, is a necessity doctrine, not for Applicants’ convenience. See Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993). Appropriate action is required.
In addition, claim 11 is indefinite because Table 1 includes antigen doublets and triplets where one or more of the antigens are NOT expressed. See the first entry of Table 1. It is currently unclear how an engineered immune cell can be modified to produce at least two different polypeptides that bind to an antigen doublet or triplet when one or more of these antigens is not expressed on the target cell.
Claim Rejections - 35 USC § 103
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 (i.e., changing from AIA to pre-AIA ) 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.
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.
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Chaudhary et al. (WO2017172981) in view of Bailucha et al. (Cancer Discov 1 September 2017; 7 (9): 1030–1045. Doi: 10.1158/2159-8290.CD-16-1414) and Cho et al. (Sci Rep. 2018 Mar 1;8(1):3846. doi: 10.1038/s41598-018-22252-6).
Claim 11 recites a method of killing a target cancer cell in a subject comprising administration of a engineered cytotoxic immune cell that expressed at least two different polypeptide, one of which binds to CDH6 and the other binds to AXL, wherein the cancer cell expresses CDH6 and AXL, and wherein one polypeptide is a BTTS and the other is a CAR.
Chaudhary et al. teaches an anti-CDH6 chimeric antigen receptor (claim 12, Table 19, ¶[0060]): “…comprising conventional CAR I and K13-vFLIP, wherein the antigen specific domain of the CAR targets CDH6…”. Chaudhary et al. additionally teaches methods of treating CDH6 expressing cancer cells comprising administration of immune effector cells such as T-cells engineered to express an anti-CDH6 CAR (¶[00535]): “[i]n one aspect, the present invention provides methods of treating or preventing a disease by providing to the subject in need thereof immune effector cells (e.g., T cells, NK cells) that are engineered to express a CDH6-specific conventional CAR…wherein the disease causing or disease associated cells express CDH6. In one embodiment, the disease to be treated or prevented is a cancer. In one embodiment, the cancer to be treated or prevented is a solid tumor.”
Bailucha et al., in the same field of endeavor, teaches that ovarian carcinomas have increased cadherin-6 expression (Introduction and Fig 1A, cropped below): “[i]n our analysis, cadherin-6 (CDH6) was a top target candidate gene featuring frequent elevated mRNA expression in ovarian serous carcinoma and restricted expression across normal tissues.”
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Bailucha et al. further teaches that targeting CDH6 with a therapeutic (in this case, a CDH6 ADC) reduces tumor volume in a mouse ovarian cancer tumor model (Fig. 4E, “CDH6-sulfo-SPDB-DM4”):
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Bailucha et al. teaches that ovarian carcinoma expresses CDH6, and targeting CDH6 can successfully lead to inhibition of tumor growth. Therefore, one with ordinary skill in the art would appreciate that CDH6 is a target to treat ovarian carcinoma with the anti-CDH6 CAR-T cell treatment method taught by Chaudhary et al.
Neither Chaudhary et al. nor Bailucha et al. teaches methods of treating cancer comprising administration of CAR-T cells that express two polypeptides, wherein one is an anti-CDH6 CAR and the other is an anti-AXL BTTS.
Cho et al., in the same field of endeavor, teaches an anti-AXL CAR SynNotch receptor and cytotoxic T-cells expressing the receptor (i.e., “a BTTS”; Cho et al. Abstract): “…an anti-Axl synNotch generated using the same scFv can be activated with Axl expressing tumor cells.” (pg. 3): “[t]he Axl synNotch receptor is composed of the Axl scFv as the extracellular domain and notch core region fused to engineered transcription factor (tTA). Jurkat T cells were engineered to stably express Axl synNotch receptor using electroporation…”
Cho et al. further teaches that cytotoxic T-cells expressing the anti-AXL CAR receptor target and kill ovarian cancer cells (Fig. 3D), and cells expressing the AXL-SynNotch successfully bind and activate upon binding to either AXL or cells expressing AXL (Fig. 4C and 4E). Cho et al. additionally teaches that both of these receptors are made with the same extracellular domain (Methods): “Axl CAR was designed by fusing humanized Axl scFv to the hinge region of the human CD8α chain and transmembrane and cytoplasmic regions… Axl synNotch receptor was designed by fusing humanized Axl scFv to the notch core intracellular domain…” Cho et al. further teaches (Discussion): “…we developed a humanized Axl scFv from previously reported Axl monoclonal antibody by fusing variable region of heavy and light chain via a polypeptide linker. Using this Axl scFv, we successfully created the first Axl CAR and synNotch receptor, which can be valuable therapeutic reagents since Axl is overexpressed in many cancers…”
It would have been obvious to one with ordinary skill in the art, before the effective filing date of the instant application, to have combined the references of Chaudhary et al., Bailucha et al., and Cho et al. to have made a combined therapy to treat ovarian cancer comprising administration of cytotoxic T-cells engineered to express both an anti-CDH6 CAR and an anti-AXL SynNotch (i.e., the limitations of instant claim 11). One with ordinary skill in the art would have had a reasonable expectation of success because Chaudhary et al. teaches cytotoxic T-cells expressing an anti-CDH6 to treat CDH6 expressing cancers, Bailucha et al. teaches that ovarian cancer expresses CDH6 which can be targeted in treatment therapies, and Cho et al. teaches an anti-AXL SynNotch that can be used in T-cells to target AXL expressing cancers such as ovarian cancer, which one with ordinary skill would appreciate would be able to be combined into a single T-cell therapy to treat renal carcinoma. Additionally, one with ordinary skill in the art would appreciate that both the anti-CDH6 CAR and anti-AXL SynNotch could be expressed by one modified T-cell using similar methods of expressing only one of these receptors. One would have been motivated to make this change for the purposes of making a combined CAR-T and SynNotch therapy to treat ovarian cancer. It is prima facie obvious to combine two compositions each of which is taught by prior art to be useful for same purpose in order to form third composition that is to be used for very same purpose; the idea of combining them flows logically from their having been individually taught in prior art. In re Kerkhoven, 205 USPQ 1069, CCPA 1980. See MPEP 2144.06. In re Couvaras, 70 F.4th 1374, 1378-79, 2023 USPQ2d 697 (Fed. Cir. 2023) (That the two claimed types of active agents, GABA-a agonists and ARBs, were known to be useful for the same purpose—alleviating hypertension—alone can serve as a motivation to combine).
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
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.
Claim 11 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 18/708,921 (herein App ‘921). Although the claims at issue are not identical, they are not patentably distinct from each other.
App ‘921 claims engineered immune cells comprising a BTTS and a CAR that each recognize different antigens (claims 1, 2, and 4). App ‘921 additionally claims cells comprising the BTTS and CAR that recognize antigens selected from Table 1 (claims 8 and 9). Table 1 is relied upon in the disclosure to determine which antigens are encompassed by the instant claims (specification pg. 21 and 11), and the antigens CDH6 and AXL are both included.
App ‘921 claims the engineered cell can be a T-cell (i.e., “cytotoxic immune cell”; App ‘921 claim 15).
App ‘921 additionally methods of treating a subject with cancer (i.e., “killing a target cancer cell in an individual”) comprising administration of the engineered cell (claim 18).
It would have been obvious to one of ordinary skill in the art to have used the claimed immune cells of App ‘921 in the claimed method of treating a subject with cancer with a reasonable expectation of success, as one with ordinary skill in the art would appreciate that the engineered immune cells can be used to treat cancer. One would have been motivated to do so to treat cancer with the claimed immune cells.
Therefore, the invention encompassed by App ‘921 is a prima facie obvious variant of the invention encompassed by the instant claim. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claim is allowed.
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/ALEC JON PETERS/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641