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 .
Applicants’ response has been received 04/20/2026 and entered.
Claim Status
An amendment was received on 04/20/2026.
Claims 1-2,6-15, and 19-24 remain pending.
All arguments have been fully considered. This status of each prior ground of rejection is set forth below.
Status of Prior Rejections / Response to Arguments
RE: Rejections of claims 1-3, 6-14, and 23 under 35 U.S.C. 112(b):
The cancellation and/or amendments to the claims overcome the basis of the prior rejections of record. The rejections are withdrawn.
RE: Rejections of claims 1-3,6-16,19-22, and 24 under 35 U.S.C. 102 (a)(1) over Mullinax et al (WO 2020/068816 A1):
Cancellation of claims 3 and 16 renders the rejection thereof moot.
The amendment to the independent claims 1 and 15 to require, inter alia, (b) digesting the samples with one or more human or humanized enzymes comprises collagenase, hyaluronidase, and/or DNase, and …where the digest of step (b) improves total number of viable cells, the percentage of digest viability, and/or total number of CD8+ T cells following digest is effective to differentiate from Mullinax et al. Mullinax et al is silent of the use of human or humanized enzymes and the effects of the digest on the specified cell populations. The rejection is withdrawn.
RE: Rejection of claim 23 under 35 U.S.C. 103 over Mullinax et al (WO 2020/068816 A1):
The amendment to the independent claims 1 and 15 (discussed above) is effective to differentiate from Mullinax et al. The rejection is withdrawn.
RE: Provisional rejection of claims 1-3 and 11-15 under 35 U.S.C. 101, Statutory Double Patenting, as having the same scope of invention of claims 1-2, 4, 10-15 and 24 of co-pending Application No. 18/842,179:
Cancellation of claim 3 renders the rejection thereof moot.
The amendment to the independent claims 1 and 15 (discussed above) is effective to differentiate from co-pending application 18/842,179 under statutory double patenting. The rejection is withdrawn.
RE: Provisional rejection of claims 6-10, 16, and 19-24 under Non-Statutory Double Patenting, as being unpatentable over claims 3,4,6,7 and 10 of co-pending Application No. 18/842,179.
Cancellation of claim 16 renders the rejection thereof moot.
The amendment to the independent claims 1 and 15 (discussed above) is effective to obviate the rejection set forth previously over co-pending application 18/842,179 under provisional non-statutory double patenting. The rejection is withdrawn.
RE: Provisional rejection of claims 1-3,6, and 10-14 under Non-Statutory Double Patenting, as being unpatentable over claims 1-3 and 10-12 of co-pending Application No. 17/279,327 in view of Mullinax et al (WO 2020/068816 A1).
Cancellation of claim 3 renders the rejection thereof moot.
The amendment to the independent claim 1 (discussed above) is effective to obviate the rejection set forth previously over co-pending application 17/279,327 under provisional non-statutory double patenting. The rejection is withdrawn.
RE: Provisional rejection of claims 15-16,19, and 23-24 under Non-Statutory Double Patenting, as being unpatentable over claims 13 and 20 of co-pending Application No. 17/279,327.
Cancellation of claim 16 renders the rejection thereof moot.
The amendment to the independent claim 15 (discussed above) is effective to obviate the rejection set forth previously over co-pending application 17/279,327 under provisional non-statutory double patenting. The rejection is withdrawn.
RE: Provisional rejection of claim 15 under Non-Statutory Double Patenting, as being unpatentable over claims 12 of co-pending Application No. 16/610,681.
The amendment to the independent claim 15 (discussed above) is effective to differentiate from co-pending application 16/610,681 under provisional non-statutory double patenting. The rejection is withdrawn.
New Grounds of Rejections
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.
Claims 1-2,6-15, and 19-24 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement.
The claims contain 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.
Applicant’s specification is not found to enabling for a method of rapidly producing an expanded tumor reactive tumor infiltrating lymphocytes (TIL) population for use in adoptive cell therapy comprising: (a)-(c), wherein the digesting in step (b) improves the total number of viable cells following digest, the percentage of digest viability, and/or the number of total CD8+ T cells following digest, compared to a digesting not using the one or more human or humanized enzymes, of claim 1 nor a method of treating cancer in a human subject comprising;(a)-(e), wherein the digesting in step (b) improves the total number of viable cells following digest, the percentage of digest viability, and/or the number of total CD8+ T cells following digest, compared to a digesting not using the one or more human or humanized enzymes, of claim 15. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to carry out the method of the invention commensurate in scope with the current claims.
Analysis of whether a particular claim is supported by the disclosure in an application requires a determination of whether that disclosure, when filed, contained sufficient information regarding the subject matter of the claims as to enable one skilled in the pertinent art to make and use the claimed invention without undue or unreasonable experimentation. See Mineral Separation v. Hyde, 242 U.S. 261, 270 (1916). The key word is 'undue,' not experimentation.' " (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required are summarized In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988). The 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 these factors are considered, a sufficient number are discussed below so as to create a prima facie case.
Applicants’ claims are directed to methods that require provision of non-purified tumor digest from one or more tissue samples that is then digested with one or more human or humanized enzymes (collagenase, hyaluronidase, and/or DNase), such that the digestion with the human or humanized enzyme(s) improves the total number of viable cells following digest, improves the percentage of digest viability, and/or the total number of CD8+ T cells following digest when compared to digest of samples with non-human/humanized enzymes.
The issue at hand is the clause stating that human/humanized enzymes improves total number of viable cells, percentage of digest viability, and/or the total number of CD8+ T cells following digest when compared to digest of samples with non-human/humanized enzymes.
The specification teaches that the total number of viable cels in tumor digest when using FDA-approved (non-Xeno) enzymes (these are human or humanized enzymes as described in the specification (See, SPEC p18 ¶50)) is less than when using research grade (non-human/humanized) enzymes, exemplified in figure 3 of the specification. Figure 4 of the specification teaches that the percentage of digest viability of the digest using FDA-approved (non-Xeno) enzymes is less than when using research grade enzymes. The total number of CD8+ T cells is not provided but the percentage of CD8+ +DE44+ cells in Figure 4, suggest that the digest with human /humanized enzymes is less than the research grade, as the total number would have a corresponding trend. The data presented in Figure 3 and 4 of the specification does not correlate with the limitations of claim 1 and 15; instead it outright contradicts the claimed effects.
Looking to the state of the art, at the time the application was filed:
Volovitz et al (BMC neuroscience, 2016) teaches dissociation of brain tumors into single cells by mechanical and enzymatic dissociation and compared it to other methods (See, Abstract). Volovitz et al teaches that brain tumors (BT) were cleansed and cut into 1-2 mm pieces, then digested in a mixture of DNase I, Collagenase and hyaluronidase (DCH), or dispase II (Disp), or papain (See, Methods p 2 paragraph 2). The collagenase type IV is derived from Clostridium histolyticum, as Xiaflex® is, a human or humanized collagenase (See, SPEC p18 ¶50) and evidenced by Chong et al (Translational andrology and urology, 2016) (See, Abstract). Figure 1a of Volovitz et al teaches the percent viability of each digestion method and that digestion with dispase II has a higher percentage viability than DCH. This directly contradicts the claim limitations and corresponds with data in the figure 3 of the specification.
Alekseeva et al ( International journal of molecular sciences, 2021) teaches that cell viability of B16 melanoma cells between cells digested with Pulmozyme® (human/humanized DNase I enzyme) and DNase I generated similar results at different concentrations but both decreased the amount of cell free DNA (See, p3 paragraph 4 and Figure 1a). This directly contradicts the claim limitations and corresponds with data in the figure 3 of the specification.
The state of the art at the time of the invention demonstrates that the use of the human or humanized enzymes does not results in the improvement of cell viability, as the claim limitations dictates.
Therefore, due to the fact the specification and prior art teach the opposite of what is claimed, one of ordinary skill in the art, at the time the invention was made, would not expect success carrying out the claimed method of rapidly producing an expanded tumor reactive tumor infiltrating lymphocytes (TIL) population for use in adoptive cell therapy (claim 1) and of treating cancer in a human subject (claim 15), such that the digest with human or humanized enzymes would improve total number of viable cells, percentage of digest viability, and/or the total number of CD8+ T cells following digest when compared to digest of samples with non-human/humanized enzymes. Given that the art and the specification teach the opposite of what is claimed, the skilled artisan would be faced with the impermissible burden of undue experimentation in order to practice the claimed invention in a manner that would achieve a tumor digest with human or humanized enzymes, wherein it improves total number of viable cells, percentage of digest viability, and/or the total number of CD8+ T cells following digest when compared to digest of samples with non-human/humanized enzymes.
Accordingly claims 1-2, 6-15, and 19-24 are deemed properly rejected.
Non-statutory Double Patenting
The non-statutory 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 non-statutory 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 non-statutory 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 non-statutory 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.
Claims 1,2,6-15,and 19-24 are provisionally rejected on the ground of non-statutory double patenting as being unpatentable over claims 4,5,6,7,10,11,12,13,14,15, and 24-28 of co-pending Application No. 18/842,179 (reference application).
Regarding claim 1: Reference claim 1 recites a method of rapidly producing an expanded tumor reactive tumor infiltrating lymphocytes (TIL) population for use in adoptive cell therapy comprising culturing bulk, non- purified tumor digest from a human subject in a culture medium comprising IL-2 in an amount effective to expand tumor-infiltrating lymphocytes with enriched tumor-reactivity; reference claim 3 recites the method of claim 1, further comprising obtaining one or more tissue samples from a subject and digesting the one or more tissue samples with a combination of two human or humanized enzymes; reference claim 4 recites the method of claim 3, wherein the combination of two human or humanized enzymes; comprises at least one of the human or humanized enzymes is selected from the group consisting of collagenase, hyaluronidase, or DNase; reference claim 5 recites the method of claim 4, wherein the combination of two human or humanized enzymes comprise a combination of two enzymes selected from the group consisting of HYLENEX®, PULMOZYME®, and XIAFLEX®. Although the claims at issue are not identical, they are not patentably distinct from each other because the active steps of the method of the reference application claims 4 and 5 encompass the scope of instant claim 1. Both applications require obtaining one or more tissue samples, digesting with human or humanized enzymes. While the reference application is silent on the effect of the digestion with the cell viability, digest viability or the CD8+ T cells in the digest when compared to non-human or humanized enzyme digestions, with the method having the same active steps, the resulting effects should necessarily be the same. Thus the claim is rendered obvious over the co-pending application.
Regarding claim 2: Following the discussion above, reference application claim 2 recites the method of claim 1, wherein an expanded TIL population also has enriched tumor specificity. Although the claims at issue are not identical, they are not patentably distinct from each other because the steps provided in the reference application and the limitations covered by Mullinax et al, read on the limitations of claim 2 of instant application, when combined with the limitations of reference claims 3 and 4, instant claim 2 is rendered obvious over the co-pending application.
Regarding claim 6: Reference claim 6 recites the method of claim 3, wherein the one or more tissue samples comprise one or more core biopsy tissue samples or one of more surgical resections. Although the claims at issue are not identical, they are not patentably distinct from each other because reference claim 6 recites limitations that encompass the scope of instant claim 6, thus the claim is rendered obvious over the co-pending application.
Regarding claims 7 and 9: Reference claim 7 recites the method of claim 6, further comprising performing one or more core biopsies or one of more surgical resections before digesting the tissue sample. Although the claims at issue are not identical, they are not patentably distinct from each other because the combination of reference claim 4 (see above) and reference claim 7 renders the two instant claims 7 and 9 obvious over the co-pending application.
Regarding claim 8: Reference claim 7 recites the method of claim 6, further comprising performing one or more core biopsies or one of more surgical resections before digesting the tissue sample. Although the claims at issue are not identical, they are not patentably distinct from each other because reference claim 7 recites limitations that encompass the scope of instant claim 7, thus the claim is rendered obvious over the co-pending application.
Regarding claim 10: Reference claim 10 recites the method of claim 3,wherein the one or more core biopsies or one or more surgical resections are digested without disaggregating the specimen. Although the claims at issue are not identical, they are not patentably distinct from each other because reference claim 10 recites limitations that encompass the scope of instant claim 10, thus the claim is rendered obvious over the co-pending application.
Regarding claim 11: Following the discussion above, reference claim 1 recites …(c) expanding the TILs directly from the bulk, non-purified tumor digest in a complete culture medium consisting of IL-2 in an amount effective to expand TILs with enriched tumor-reactivity. Although the claims at issue are not identical, they are not patentably distinct from each other because the steps provided in the reference application and the specificity of tissue sample used in a similar method read on the limitations of claim 11 of instant application, thus instant claim 11 is rendered obvious over the co-pending application.
Regarding claim 12: Following the discussion above, reference claim 10 recites the method of claim 1, further comprising harvesting the expanded TIL population. Although the claims at issue are not identical, they are not patentably distinct from each other because the steps provided in the reference application and the specificity of tissue sample used in a similar method read on the limitations of claim 12 of instant application, thus instant claim 12 is rendered obvious over the co-pending application.
Regarding claim 13: Following the discussion above, reference claim 11 recites the method of claim 1, wherein the TILs are cultured in media consisting of IL-2 for 5 weeks or less. Although the claims at issue are not identical, they are not patentably distinct from each other because the steps provided in the reference application and the specificity of tissue sample used in a similar method read on the limitations of claim 13 of instant application, thus instant claim 13 is rendered obvious over the co-pending application.
Regarding claim 14: Following the discussion above, reference claim 12 recites a method of treating a cancer in a subject comprising administering to the subject a rapidly expanded TIL population made by the method of claim 1. Although the claims at issue are not identical, they are not patentably distinct from each other because the steps provided in the reference application and the specificity of tissue sample used in a similar method read on the limitations of claim 14 of instant application, thus instant claim 14 is rendered obvious over the co-pending application.
Regarding claim 15: The instant claim is identical in scope to claim 15 of the reference application, as both claims recite a method of treating cancer in a human subject comprising culturing bulk, non-purified tumor digest from the subject in a culture medium comprising IL-2 in an amount effective to expand tumor-infiltrating lymphocytes (TILs) with enriched tumor- reactivity and/or specificity; harvesting the expanded TIL cells; and adoptively transferring to the subject the expanded TILs. Reference claims 3 and 4 (set forth above), recite a similar method with the added limitations of obtaining samples from a subject and digesting the samples in human or humanized enzymes. It would have been obvious to a person of ordinary skill to substitute the generic enzymes of reference claim 15 with the human/ humanized ones of reference claims 3 or 4 for the immunogenic benefits for treatment.
Although the claims at issue are not identical, they are not patentably distinct from each other because the active steps of the method of the reference application claims 15, 3, 4 and 5 encompass the scope of instant claim 15. Both applications require obtaining one or more tissue samples, digesting with human or humanized enzymes. While the reference application is silent on the effect of the digestion with the cell viability, digest viability or the CD8+ T cells in the digest when compared to non-human or humanized enzyme digestions, with the method having the same active steps, the resulting effects should necessarily be the same. Thus the claim is rendered obvious over the co-pending application.
Regarding claims 19-22: Reference claims 4 recites the method of claim 3, wherein the combination of two human or humanized enzymes; comprises at least one of the human or humanized enzymes is selected from the group consisting of collagenase, hyaluronidase, or DNase. Reference claim 6 recites the method of claim 3, wherein the one or more tissue samples comprise one or more core biopsy tissue samples or one of more surgical resections. Reference claim 7 recites the method of claim 6, further comprising performing one or more core biopsies or one of more surgical resections before digesting the tissue sample. Reference claim 15 recites the reference application, as both claims recite a method of treating cancer in a human subject comprising culturing bulk, non-purified tumor digest from the subject in a culture medium comprising IL-2 in an amount effective to expand tumor-infiltrating lymphocytes (TILs) with enriched tumor- reactivity and/or specificity; harvesting the expanded TIL cells; and adoptively transferring to the subject the expanded TILs. Although the claims at issue are not identical, they are not patentably distinct from each other because the combination of reference claims 4,6,7, and 15 renders the two instant claims 19-22 obvious over the co-pending application.
Regarding claim 23: Reference claims 4,6, and 15 are recited above. Reference claim 10 recites the method of claim 3,wherein the one or more core biopsies or one or more surgical resections are digested without disaggregating the specimen. Although the claims at issue are not identical, they are not patentably distinct from each other because the combination of reference claims 4,6,10, and 15 renders the instant claim 23 obvious over the co-pending application.
Regarding claim 24: Reference claim 24 recites the method claim 14,wherein the cancer is a solid tumor. Reference claims 25-28 are all examples of solid tumors that would read on the instant claim 24. Reference claim 15 recites the limitations of needed for the instant claim 24 (see above), therefore although the claims at issue are not identical, they are not patentably distinct from each other because the combination of reference claims 15 and 24-28 renders the instant claim 24 obvious over the co-pending application.
This is a provisional non-statutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
Applicant's amendment necessitated the new grounds of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Caroline M Lara whose telephone number is (571)272-4262. The examiner can normally be reached 7:00 to 4:30pm M-Th.
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/CAROLINE M LARA/Examiner, Art Unit 1633
/ALLISON M FOX/Primary Examiner, Art Unit 1633
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