Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Claims 1-2, 10-13, and 20-24 are pending in the instant application.
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 2/7/2025 has been entered.
Rejections Withdrawn
The rejections to claims 5, 9, and 16 are moot in view of claim cancelation.
The rejection of claims 1-2, 10-13, and 20-24 under 35 U.S.C. 112(b) is withdrawn in view of claim amendment.
The rejection of claims 1-2, 10-13, and 20-24 under 35 U.S.C. 103 is withdrawn in view of claim amendment.
The rejection of claims 1-2, 10-13, and 20-24 under nonstatutory double patenting is withdrawn in view of claim amendment.
Claim Interpretation
The term “disaggregating” is not defined in the specification and the Examples utilize minced tumor fragments prior to digestion and mechanical disruption following digestion. The term “disaggregating” will be defined as “converting the harvested tumor into a single-cell suspension for biologic analysis without altering the phenotype or functional activity of the target cell population” as defined by Quatromoni JG et al. (Journal of Leukocyte Biology, 2015 97(1) 201–209), page 201, left column last paragraph to right column first paragraph). Further, “disaggregating” into a single-cell suspension will be defined to require the purification of TILs from tumor digest, wherein prior to rapid expansion, TILs are purified and separated from other cells within the tumor, and cultured as a purified TIL culture prior to a rapid expansion step.
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 1-2, 10-13, 16, and 20-24 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.
Regarding instant claims 1 and 13, the meets and bounds of the claim are unclear because:
Claims 1 and 13 claim that an expansion is performed on the non-purified tumor digest in a complete culture medium consisting of IL-2, but the tumor digest in the culture medium further comprises a digestion solution of one or more enzymes. The meets and bounds of the complete culture medium are indefinite and unclear because the bulk, non-purified tumor digest must contain enzymes to be non-purified, but the complete medium is also required to consist of IL-2. Claimed complete medium that consists of IL-2 would only consist of IL-2 as the medium. No other components would be within the medium in order to consist of IL-2. Thus, the claims are indefinite and the meets and bounds are unclear. To promote compact prosecution, in claims 1 and 13, the culture medium will be interpreted as ---comprising of IL-2--- not “consisting of IL-2”. The instant specification taught culturing TILs in complete media comprising IL-2 (specification, page 9, paragraph 13).
Claims 1 and 13 claim a process method but do not clearly claim a series of action steps for performing the method. Claim 1 step (a) requires obtaining one or more bulk, non-purified tumor digests from a core biopsy tissue sample, but step (b) requires digesting the one or more core biopsy tissue samples with one or more enzymes to form a bulk, non-purified tumor digest. Thus, step (b) occurs prior to step (a). Claim 13 step (c) does not clearly indicate if the excess of the bulk, non-purified tumor digest is from step (a) or step (b). To promote compact prosecution: i) in claim 1, step (a) will be exchanged with ---obtaining one or more core biopsy tissue samples--- ; ii) in claim 13, “contacting an excess of the bulk, non-purified tumor digest” will be exchanged with ---contacting an excess of the bulk, non-purified tumor digest in step (a)--- .
Claims 2, 10-12, 16, and 20-24 depend on claims 1 and 13 and therefore further contain the indefinite subject matter and are rejected.
Regarding instant claim 1, a conjunction of ---and--- or ---or--- is not present in claim 1 between steps (b) and (c). Thus, it is unclear if all the steps are required or if the steps are required in the alternative. To promote compact prosecution, in claim 1, a conjunction of ---and--- will be interpreted between steps (b) and (c).
Claims 2 and 10-12 depend on claim 1 and therefore further contain the indefinite subject matter and are rejected.
Regarding instant claim 13, the method requires a core biopsy, but also requires a fine needle. The instant specification indicates core biopsies are obtained from core needles with a needle gauge of 20 or less (specification, pages 9-10, paragraphs 16-17). Thus, the claim is indefinite and the meets and bounds are unclear. Claims 20-24 depend on claim 13 and therefore further contain the indefinite subject matter and are rejected.
Claim 11 recites the limitation "media consisting of IL-2" in line 11. There is insufficient antecedent basis for this limitation in the claim. Claim 1 recites “complete culture medium consisting of IL-2”. To promote compact prosecution, “media” will be interpreted as ---complete culture medium--- .
Claim Rejections – 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 2 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 2, recites outcomes of the claimed methods of claim 1, but does not have active method steps that further narrow the claimed methods. The claimed method of claim 1 has been shown to demonstrate the effects recited in claim 1, but there are no further steps that individually vary the effects recited in claim 2. Thus, claim 2 does not further narrow claim 1. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections – 35 USC § 112(a)
Claims 1-2, 10-13 and 20-24 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 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.
Regarding instant claims 1 and 13, new matter is claimed wherein: i) claim 1 step (a) claims more than one digest from a core biopsy, which would encompass a single core biopsy; and ii) claim 13 step (c) wherein an action of contacting an excess of the bulk, non-purified tumor digest with a digestion solution to obtain additional TILs is performed. The Applicant did not disclose a step of multiple rounds of digestion of a core biopsy in the originally filed disclosure or priority documents. The instant specification filed 3/24/2021 discloses a digestion of multiple samples which includes core needle biopsies and digestion with one or more enzymes (pages 1-2, paragraph 5), as well as a single digestion of excess tumor tissue that was not previously digested (page 17, paragraph 47), but fail to disclose multiple separate digestions of a core biopsy or excess tumor tissue.
Claims 2, 10-12, and 20-24 further include the new matter and are also rejected.
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.
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.
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.
Claims 1-2 and 10-12 are rejected under 35 U.S.C. 103 as being unpatentable over US 20180282694 (Wardell S et al. effective filing date 3/29/2017 reference of record), US 20190276802 (Simpson-Abelson MR et al. effective filing date 11/17/2016 reference of record), Panelli MC et al. (J Immunol 2000 164 (1), 495–504 reference of record), and Ullenhag et al. (Cancer Immunol Immunother. 2011 61(5):725–732.).
Regarding instant claims 1, and 10-13 Wardell taught a method comprising rapid expansion (REP) of a tumor infiltrating lymphocytes (TIL) population for use in adoptive cell therapy, wherein the method comprises:
culturing and performing an expansion of the TILs directly from a bulk, non-purified tumor fragment from a subject in a culture medium comprising IL-2 in an amount effective to expand TILs with enriched tumor-reactivity, wherein the bulk, non-purified tumor comprises a surgical tumor resection obtained from the subject for 11 days,
culturing the cells with a Rapid Expansion Protocol (REP), wherein TIL are cultured with feeders and OKT3 for REP expansion for an additional 11 days;
harvesting the TIL;
administering the TIL to the subject with the tumor
(page 8, paragraph 195 and FIG. 68).
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Regarding instant claims 1 and 13, Wardell taught TILs can be initially cultured from enzymatic tumor digests and tumor fragments obtained from patients (page 18, paragraph 323). Regarding instant claims 1 and 13, Wardell taught a patient tumor sample may be a surgical resection or needle biopsy, wherein the sample contains a mixture of tumor and TIL cells (page 17, paragraph 318). Regarding instant claims 1 and 13, Wardell taught the tumor digests are incubated in 2 mL wells in media comprising inactivated human AB serum with IL-2 (page 18, paragraph 323), which would be a complete media. Wardell taught culture of TILs in a complete culture medium containing IL-2 was effective for expanding TILs (page 78, paragraph 1628-1630).
Wardell taught Adoptive T-cell therapy with autologous tumor infiltrating lymphocytes (TIL) has demonstrated clinical efficacy in patients with metastatic melanoma and other tumors (page 114, paragraph 2385). Regarding instant claims 20-24, Wardell taught the solid tumor may be of any cancer type (page 17, paragraph 318) including a sarcoma (page 15, paragraph 295).
Wardell did not teach: a) a single embodiment wherein bulk tumors are digested and cultured directly; b) the needle biopsy as a core needle biopsy, but this is obvious in view of Simpson-Abelson, Panelli, and Ullenhag.
Simpson-Abelson taught TILs may be cultured from enzymatic tumor digests and tumor fragments from sharp dissection (page 19, paragraph 503). Simpson-Abelson taught for enzymatic digestion of solid tumors; tumor specimens were resuspended in enzymatic digestion buffer followed by rotation (page 21, paragraph 521 and Fig. 2). Rotation of the enzymatic digest is a mechanical disruption of the tumor. Simpson-Abelson taught methods of delivering a therapeutically effective amount of an expanded number of tumor infiltrating lymphocytes obtained from tumor remnants to a patient in need thereof, for the treatment of a cancer (abstract). Simpson-Abelson taught using a MACS TDK enzymatic digest procedure, wherein the digest procedure caused poor yield and viability of rTILs was inferior to a procedure with DCH digest (page 34, paragraph 724). Simpson-Abelson taught following digestion with DCH solid material can remain in the cell strainer (page 34, paragraph 722). Simpson-Abelson taught during pre-REP of tumor fragments for TIL expansion, tumor-resident TILs emigrate as emigrating TILs (eTILs) and proliferate (page 34, paragraph 725). Simpson-Abelson taught viable TILs remaining in the tumor remnants (rTILs) following the pre-REP were investigated after digestion (page 34, paragraph 725), wherein enzymes are used (page 33, paragraph 719) and rTILs within digested bulk tumor are consistently phenotypically distinct from eTILs (page 34, paragraph 725), and rTILs in the digested tumor were identified to have desirable properties wherein A) rTILs are less terminally differentiated than eTILs (i.e., less likely to die) (pages 34-35, paragraph 728); B) rTIL have lower expression of “exhaustion markers” (LAG3 and TIM3) (page 35, paragraph 729). Simpson-Abelson taught as observed prior to REP, the eTILs and rTILs obtained post-REP were phenotypically distinct, wherein many of the phenotypic differences observed in the pre-REP were preserved during the REP, such as a reduction in LAG3 and TIM3 expression in the rTIL (page 35, paragraph 734 and FIG. 6B). Simpson-Abelson taught the eTIL from either the CD4+ or CD8+ population in melanoma and renal, colorectal, breast, and lung cancer tumors demonstrated an enhancement in the proliferative capacity upon co-culture with rTIL with anti-CD3 antibody when compared to eTIL alone (page 36, paragraph 744 and Fig 11). Simpson-Abelson taught the diversity of the TCRvβ repertoire is greater in the rTIL than in the eTIL (FIG. 9), wherein about 30-50% of the total CDR3 in the eTIL and rTIL are shared (FIG. 10), demonstrating that a large percentage of the total CDR3's are differentially expressed in the two populations (page 36, paragraph 741).
Panelli taught TIL expansion in bulk tumor biopsies, wherein tumor cells, RBC, and TILs were present in a 24-well plate with a complete culture medium comprising Iscove’s medium and 6000 IU/ml IL-2, wherein CD4+ and CD8+ cells were obtained (page 496, right column, third paragraph and Table 2 legend). Panelli taught biopsy expanded TILs could recognize autologous tumor cells (Fig. 1).
Ullenhag taught a successful method of obtaining tumor-infiltrating lymphocytes (TIL) from a tumor in a patient via a core needle biopsy (abstract). Ullenhag taught needle biopsies obtained with an 18 gauge needle that were 2 cm long (page 726, right column, first paragraph).
Regarding instant claims 1-2 and 10-12, it would have been obvious for a person having ordinary skill in the art to take the method of Wardell for adoptive transfer treatment of a subject with expanded TIL comprising rapid expansion (REP) of a tumor infiltrating lymphocytes (TIL) population for use in adoptive cell therapy, wherein the method comprises:
surgically excising a tumor and culturing and performing an expansion of the TILs directly from a bulk, non-purified tumor fragmented sample from a subject, wherein the tumor is a sarcoma, in a complete culture medium comprising IL-2 in an amount effective to expand TILs with enriched tumor-reactivity, wherein the bulk, non-purified tumor comprises a surgical tumor resection obtained from the subject for 11 days,
culturing the cells with a Rapid Expansion Protocol (REP), wherein TIL are cultured with feeders and OKT3 for REP expansion for an additional 11 days;
harvesting the expanded TIL population; and
administering the TIL to the subject with the tumor for treatment;
– and: 1) select a patient tumor sample that is a core needle biopsy as taught by Ullenhag;
2) initially culture enzymatic tumor digests from the patient sample as taught by Wardell, wherein the enzymatic digestion of solid tumors includes a step of resuspension in enzymatic digestion buffer and rotation of the digest as taught by Simpson-Abelson,
3) culture the initial tumor digests in 2 mL wells in a complete culture medium comprising IL-2 as taught by Wardell; and
4) culture the sample fragment without previous disaggregation into a purified TIL population as taught by Wardell, Simpson-Abelson, and Panelli.
This is obvious because: 1) Wardell taught a needle biopsy and Ullenhag taught a successful method of obtaining tumor-infiltrating lymphocytes (TIL) from a tumor in a patient via a core needle biopsy; 2)-4) Wardell taught these as embodiments of the method; 2) Simpson-Abelson taught enzymatic digestion of solid tumors includes a step of resuspension in enzymatic digestion buffer and rotation of the digest; and 3-4) Panelli taught TIL expansion in bulk tumor biopsies, wherein tumor cells, RBC, and TILs were present in a 24-well plate with a complete media comprising IL-2, wherein CD4+ and CD8+ cells were obtained and wherein the biopsy expanded TILs could recognize autologous tumor cells. Thus, tumor cells and RBC did not negatively affect TIL expansion.
There is a reasonable expectation of success because: 1) Ullenhag taught a successful method of obtaining tumor-infiltrating lymphocytes (TIL) from a tumor in a patient via a core needle biopsy and TILs have been shown to be successfully expanded wherein the TILs can recognize the tumor cells; 2) enzymatic digests of bulk tumor samples with resuspension and rotation culture eTIL and rTIL which are phenotypically distinct, wherein rTIL have desirable properties and the co-culture of eTIL and rTIL promote further eTIL proliferation as taught by Simpson-Abelson; 3) Wardell taught culture of TILs in a complete culture medium containing IL-2 was effective for expanding TILs; and
4) Wardell used a tumor fragment and did not disaggregate and purify the TILs from the tumor for pre-rapid expansion culture. Further, Panelli taught effective TIL expansion in bulk tumor biopsies, wherein tumor cells, RBC, and TILs were present in a 24-well plate with a complete culture medium comprising IL-2, wherein CD4+ and CD8+ cells were obtained and wherein the biopsy expanded TILs could recognize autologous tumor cells.
This would produce a method for adoptive transfer treatment of a subject with expanded TIL comprising rapid expansion (REP) of a tumor infiltrating lymphocytes (TIL) population for use in adoptive cell therapy, wherein the method comprises:
obtaining a core needle biopsy of a sarcoma tumor from a subject;
enzymatically digesting the fragments without previous disaggregation to a purified TIL population;
culturing and performing an expansion of the TILs directly from a bulk, non-purified digested tumor sample from the subject in a complete culture medium comprising IL-2 in an amount effective to expand TILs with enriched tumor-reactivity for 11 days;
culturing the cells with a Rapid Expansion Protocol (REP), wherein TIL are cultured with feeders and OKT3 for REP expansion for an additional 11 days;
harvesting the expanded TIL population (instant claim 10); and
administering the TIL to the subject for adoptive transfer for treatment of the tumor (instant claim 12).
This method would naturally produce an expanded population of TILs with enriched tumor specificity with an increased TCRvβ repertoire (instant claim 2), wherein the period of time IL-2 is cultured with the TILs is 22 days, which is less than 5 weeks (instant claim 11). This further meets the claim limitations of instant claim 1.
Response to Arguments
The claims have been amended and new grounds of rejection are above.
Claims 1-2, 10-13, and 20-21 are rejected under 35 U.S.C. 103 as being unpatentable over US 20180282694 (Wardell S et al. effective filing date 3/29/2017 reference of record), US 20190276802 (Simpson-Abelson MR et al. effective filing date 11/17/2016 reference of record), Panelli MC et al. (J Immunol 2000 164 (1), 495–504 reference of record), and Ullenhag et al. (Cancer Immunol Immunother. 2011 61(5):725–732.) as applied to claims 1-2 and 10-12 above, and further in view of Petit V et al. (Laboratory Investigation 2013 93, 611–621).
Wardell, Simpson-Abelson, Panelli, and Ullenhag are described above.
Regarding instant claims 20-24, Wardell further taught the solid tumor may be of any cancer type (page 17, paragraph 318) including a sarcoma (page 15, paragraph 295).
Regarding instant claim 13, Simpson-Abelson further taught for enzymatic digestion of solid tumors; tumor specimens were resuspended in enzymatic digestion buffer followed by rotation (page 21, paragraph 521 and Fig. 2). Simpson-Abelson taught following digestion with DCH solid material can remain in the cell strainer (page 34, paragraph 722).
Regarding instant claim 13, Ullenhag taught a successful method of obtaining tumor-infiltrating lymphocytes (TIL) from a tumor in a patient via a core needle biopsy (abstract). Ullenhag taught needle biopsies obtained with an 18 gauge needle that were 2 cm long (page 726, right column, first paragraph). Thus, obtaining a core needle biopsy tissue sample of 2 cm (20 mm) from a 30 mm tumor within a subject would require the needle penetrate the tumor at a depth between about 20 and 30 mm to obtain the core biopsy tissue sample aspirate.
Wardell did not teach: 1) the depth of the needle biopsy: or 2) a method comprising more than one digestion of tumor fragments then pooling the tumor digestions, but this is obvious in view of Simpson-Abelson, Panelli, Ullenhag, and Petit.
Petit taught an effective method of tumor tissue dissociation comprising: a) digesting tumor fragments in an enzyme solution; b) filtering the digestion solution through a cell strainer; c) further digesting the tumor fragments that remained in the strainer in a digestion solution; d) pooling the tumor digestions (pages 612-613 bridging paragraph and Fig. 1).
Regarding instant claims 13 and 20-21, it would have been obvious for a person having ordinary skill in the art to take the method of Wardell, Simpson-Abelson, Panelli, and Ullenhag above comprising:
obtaining a core needle biopsy of a sarcoma tumor from a subject;
enzymatically digesting the core needle tumor sample without previous disaggregation to a purified TIL population;
culturing and performing an expansion of the TILs directly from a bulk, non-purified digested tumor sample from the subject in a complete culture medium comprising IL-2 in an amount effective to expand TILs with enriched tumor-reactivity for 11 days;
culturing the cells with a Rapid Expansion Protocol (REP), wherein TIL are cultured with feeders and OKT3 for REP expansion for an additional 11 days;
harvesting the expanded TIL population; and
administering the TIL to the subject for adoptive transfer for treatment of the tumor,
– and modify the method to: 1) perform a core biopsy of a tumor wherein the tumor biopsy depth is between 20 and 30 mm, and wherein the tumor is 30 mm in view of Ullenhag; and 2) include a) a first round of digesting tumor fragments in an enzyme solution; b) filtering the digestion solution through a cell strainer to obtain excess non-digested tumor fragments; c) further digesting the excess digested tumor fragments that remained in the strainer in a digestion solution; and d) pooling the tumor digestions in view of Petit.
This is obvious because: 1) Ullenhag taught needle biopsies obtained with an 18 gauge needle that were 2 cm (20 mm) long and for a tumor that had a diameter of 30 mm, the 20 mm long core needle biopsy of the tumor would require a depth of 20 to 30 mm to obtain a tumor sample; and 2a) Simpson-Abelson taught following enzymatic digestion with DCH, solid material can remain in the cell strainer; 2b) Simpson-Abelson taught viable TILs are within tumor remnants (rTILs) that were effective; and 2c) Petit taught an effective method of tumor tissue dissociation comprising: a) enzymatically digesting tumor fragments in an enzyme solution; b) filtering the enzymatic digestion solution through a cell strainer; c) further digesting the tumor fragments that remained in the strainer in an enzymatic digestion solution; and d) pooling the tumor digestions.
There is a reasonable expectation of success because: 1a) Ullenhag taught a successful method of obtaining TIL from a tumor in a patient via a core needle biopsy, wherein needle biopsies were obtained with an 18 gauge needle that were 2 cm (20 mm) long; 1b) for a tumor that had a diameter of 30 mm, the 20 mm long core needle biopsy of the tumor would require a depth of 20 to 30 mm to obtain a tumor sample;
2a) Simpson-Abelson taught following enzymatic digestion with DCH, solid material can remain in the cell strainer and effective rTILs are known to be within the tumor. Thus, enzymatic digestion of the core sample then further enzymatic digestion of the excess tumor fragments that remained from the core biopsy, would allow more rTILs to be obtained from the core biopsy that could be pooled for expansion; 2b) Petit taught an effective method of tumor tissue dissociation comprising: a) enzymatically digesting tumor fragments in an enzyme solution; b) filtering the digestion solution through a cell strainer; c) further enzymatically digesting the tumor fragments that remained in the strainer in a digestion solution; and d) pooling the tumor digestions.
This would produce a method for adoptive transfer treatment of a subject with expanded TIL comprising rapid expansion (REP) of a tumor infiltrating lymphocytes (TIL) population for use in adoptive cell therapy, wherein the method comprises:
obtaining a core needle biopsy aspirate of a sarcoma tumor from a subject (instant claims 20-21), wherein a core needle biopsy tissue sample of 2 cm (20 mm) from a 30 mm tumor is obtained from a subject which requires the needle to penetrate the tumor at a depth between about 20 and 30 mm to obtain the core biopsy tissue sample aspirate;
enzymatically digesting the core needle biopsy without previous disaggregation to a purified TIL population;
filtering the enzymatic digestion solution through a cell strainer to obtain excess bulk digested core needle biopsy tumor fragments;
culturing and performing an expansion of the filtered TILs directly from a bulk, non-purified digested tumor sample from the subject in a complete culture medium comprising IL-2 in an amount effective to expand TILs with enriched tumor-reactivity;
contacting the excess bulk digested core needle biopsy tumor fragments that is non-purified from the filter with an enzymatic digestion solution to obtain additional TILs from the excess digested core needle biopsy that are a bulk, non-purified tumor digest that is digested without being disaggregated;
pooling the TILs from step (d) and (e) and culturing and performing an expansion of the TILs directly from a bulk, non-purified digested tumor sample from the subject in a complete culture medium comprising IL-2 in an amount effective to expand TILs with enriched tumor-reactivity for 11 days;
culturing the cells with a Rapid Expansion Protocol (REP), wherein TIL are cultured with feeders and OKT3 for REP expansion for an additional 11 days;
harvesting the expanded TIL population; and
administering the TIL to the subject for adoptive transfer for treatment of the tumor.
This method would naturally produce an expanded population of TILs with enriched tumor specificity with an increased TCRvβ repertoire, wherein the period of time IL-2 is cultured with the TILs is 22 days, which is less than 5 weeks. This further meets the claim limitations of instant claim 13.
Response to Arguments
The claims have been amended and new grounds of rejection are above.
Claims 1-2, 10-13, and 20-24 are rejected under 35 U.S.C. 103 as being unpatentable over US 20180282694 (Wardell S et al. effective filing date 3/29/2017 reference of record), US 20190276802 (Simpson-Abelson MR et al. effective filing date 11/17/2016 reference of record), Panelli MC et al. (J Immunol 2000 164 (1), 495–504 reference of record), Ullenhag et al. (Cancer Immunol Immunother. 2011 61(5):725–732.), and Petit V et al. (Laboratory Investigation 2013 93, 611–621) as applied to claims 1-2, 10-13, and 20-21 above, and further in view of Kamamoto D et al. (J Neurooncol 2018 139, 251–259 reference of record).
Wardell, Simpson-Abelson, Panelli, Ullenhag, and Petit are described above.
Wardell does not describe the tumor sample as a solitary fibrous tumor, but this is obvious in view of Kamamoto.
Kamamoto taught CD8 was observed in TILs of 13/16 solitary fibrous tumors (abstract). Kamamoto taught diffuse PD-L1 staining coupled with no or sparse CD8 expression was significantly associated with a shorter time to treatment failure and showed a trend toward shorter metastasis free survival (abstract).
Regarding instant claims 22-24, it would have been obvious for a person having ordinary skill in the art to take the method of Wardell, Simpson-Abelson Panelli, Ullenhag, and Petit above – and 1) expand TILs from solitary fibrous tumors for adoptive cell treatment of subjects with solitary fibrous tumors.
This is obvious because: 1) CD8 was observed in TILs of 13/16 solitary fibrous tumors; and lack of TILs in the tumor showed worst outcomes.
There is a reasonable expectation of success because: 1) TILs are present in solitary fibrous tumors and can be expanded; and 2) outcomes are poor when CD8 TILs are not in the tumor so increasing the TILs by adoptive transfer would be thought to be beneficial.
Response to Arguments
The claims have been amended and new grounds of rejection are above.
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).
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Claim 1 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 6-16, and 19-24 of copending Application No. 18/555,584. Although the claims at issue are not identical, they are not patentably distinct from each other because:
Copending claims 1, 3, and 10 taught a method of rapidly producing an expanded tumor reactive infiltrating lymphocyte population in a complete culture medium comprising IL-2 for use in adoptive cell therapy, wherein digestion is performed on the sample, and wherein one or more core biopsies or surgical resections are digested without disaggregating the specimen which anticipates instant claim 1.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
The claims have been amended and new grounds of rejection are above.
Claims 1-2 and 10-12 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 6-16, and 19-24 of copending Application No. 18/555,584 in view of copending Application No. 18/555,584.
The claims of the copending ‘584 teach the limitations of claim 1 for the reasons set forth above.
Copending claims 1, 3, and 10 taught a method of rapidly producing an expanded tumor reactive infiltrating lymphocyte population in a complete culture medium comprising IL-2 for use in adoptive cell therapy, wherein digestion is performed on the sample, and wherein one or more core biopsies or surgical resections are digested without disaggregating the specimen. Regarding instant claim 2, copending claim 2 taught the method of claim 1, wherein the expanded TIL population also has enriched tumor specificity to anticipate. Copending claims 6-7 taught the method of claim 1, wherein one or more core biopsies are performed before digesting the sample. Regarding instant claim 10, copending claim 12 taught harvesting the expanded TIL population. Regarding instant claim 11, copending claim 13 taught culturing the TIL population in IL-2 comprising complete culture media for 5 weeks or less. Regarding instant claim 12, copending claim 14 taught administering the rapidly expanded TIL population and administering the TIL population to a subject. Regarding instant claim 20, copending claim 24 taught the tumor as a solid tumor.
Regarding instant claims 2 and 10-12, it would have been obvious for a person having ordinary skill in the art to take the method of copending claims 1, 3, and 10 comprising rapidly producing an expanded tumor reactive infiltrating lymphocyte population in a complete culture medium comprising IL-2 for use in adoptive cell therapy, wherein digestion is performed on the sample, and wherein one or more core biopsies or surgical resections are digested without disaggregating the specimen – and modify the method to include: 1) culturing the TIL population in IL-2 comprising complete culture medium for 5 weeks or less as taught by copending claim 13; 2) harvesting the expanded TIL population as taught by copending claim 12; 3) administer the rapidly expanded TIL population and administering the TIL population to a subject as taught by copending claim 14; 4) perform the core needle biopsy on a solid tumor as taught by copending claim 24.
This is obvious because: 1) copending claim 12 taught harvesting the expanded TIL population; 2) copending claim 13 taught culturing the TIL population in IL-2 comprising complete culture media for 5 weeks or less; 3) copending claim 14 taught administering the rapidly expanded TIL population and administering the TIL population to a subject; 4) copending claim 24 taught the tumor as a solid tumor.
There is a reasonable expectation of success because: 1) and 3) the TILs have enriched tumor-reactivity and would need to be harvested and administered for treatment; 2) The TILs are already known to be cultured in IL-2 comprising complete culture medium and copending claim 13 teaches the timing of the culture for enriched tumor-reactivity; and 4) solid tumors are known to have TILs.
This would produce a method comprising rapidly producing an expanded tumor reactive infiltrating lymphocyte population in a complete culture medium comprising IL-2 for use in adoptive cell therapy, wherein digestion is performed on the sample, and wherein one or more core biopsies or surgical resections from a solid tumor are digested without disaggregating the specimen, wherein culturing the TIL population in IL-2 comprising complete culture medium for 5 weeks or less (instant claim 11), wherein the TIL are harvested from the expanded TIL population (instant claim 10), wherein the rapidly expanded TIL population harvested is administered to a subject (instant claim 12)(instant claim 1). This method would naturally produce expanded TILs with enriched tumor specificity (instant claim 2).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
The claims have been amended and new grounds of rejection are above.
Claims 1-2, 10-13, and 20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 6-16, and 19-24 of copending Application No. 18/555,584 in view of US 20190276802 (Simpson-Abelson MR et al. effective filing date 11/17/2016 reference of record), Panelli MC et al. (J Immunol 2000 164 (1), 495–504 reference of record), Ullenhag et al. (Cancer Immunol Immunother. 2011 61(5):725–732.), and Petit V et al. (Laboratory Investigation 2013 93, 611–621).
The claims of the copending ‘584 teach the limitations of claims 1-2 and 10-12 for the reasons set forth above.
The claims of ‘584 did not teach: 1) the depth of the needle biopsy: or 2) a method comprising more than one digestion of tumor fragments then pooling the tumor digestions, but this is obvious in view of Simpson-Abelson, Panelli, Ullenhag, and Petit.
Simpson-Abelson taught TILs may be cultured from enzymatic tumor digests and tumor fragments from sharp dissection (page 19, paragraph 503). Simpson-Abelson taught for enzymatic digestion of solid tumors; tumor specimens were resuspended in enzymatic digestion buffer followed by rotation (page 21, paragraph 521 and Fig. 2). Rotation of the enzymatic digest is a mechanical disruption of the tumor. Simpson-Abelson taught methods of delivering a therapeutically effective amount of an expanded number of tumor infiltrating lymphocytes obtained from tumor remnants to a patient in need thereof, for the treatment of a cancer (abstract). Simpson-Abelson taught using a MACS TDK enzymatic digest procedure, wherein the digest procedure caused poor yield and viability of rTILs was inferior to a procedure with DCH digest (page 34, paragraph 724). Simpson-Abelson taught following digestion with DCH solid material can remain in the cell strainer (page 34, paragraph 722). Simpson-Abelson taught during pre-REP of tumor fragments for TIL expansion, tumor-resident TILs emigrate as emigrating TILs (eTILs) and proliferate (page 34, paragraph 725). Simpson-Abelson taught viable TILs remaining in the tumor remnants (rTILs) following the pre-REP were investigated after digestion (page 34, paragraph 725), wherein enzymes are used (page 33, paragraph 719) and rTILs within digested bulk tumor are consistently phenotypically distinct from eTILs (page 34, paragraph 725), and rTILs in the digested tumor were identified to have desirable properties wherein A) rTILs are less terminally differentiated than eTILs (i.e., less likely to die) (pages 34-35, paragraph 728); B) rTIL have lower expression of “exhaustion markers” (LAG3 and TIM3) (page 35, paragraph 729). Simpson-Abelson taught as observed prior to REP, the eTILs and rTILs obtained post-REP were phenotypically distinct, wherein many of the phenotypic differences observed in the pre-REP were preserved during the REP, such as a reduction in LAG3 and TIM3 expression in the rTIL (page 35, paragraph 734 and FIG. 6B). Simpson-Abelson taught the eTIL from either the CD4+ or CD8+ population in melanoma and renal, colorectal, breast, and lung cancer tumors demonstrated an enhancement in the proliferative capacity upon co-culture with rTIL with anti-CD3 antibody when compared to eTIL alone (page 36, paragraph 744 and Fig 11). Simpson-Abelson taught the diversity of the TCRvβ repertoire is greater in the rTIL than in the eTIL (FIG. 9), wherein about 30-50% of the total CDR3 in the eTIL and rTIL are shared (FIG. 10), demonstrating that a large percentage of the total CDR3's are differentially expressed in the two populations (page 36, paragraph 741).
Panelli taught TIL expansion in bulk tumor biopsies, wherein tumor cells, RBC, and TILs were present in a 24-well plate with a complete culture medium comprising Iscove’s medium and 6000 IU/ml IL-2, wherein CD4+ and CD8+ cells were obtained (page 496, right column, third paragraph and Table 2 legend). Panelli taught biopsy expanded TILs could recognize autologous tumor cells (Fig. 1).
Ullenhag taught a successful method of obtaining tumor-infiltrating lymphocytes (TIL) from a tumor in a patient via a core needle biopsy (abstract). Ullenhag taught needle biopsies obtained with an 18 gauge needle that were 2 cm long (page 726, right column, first paragraph).
Petit taught an effective method of tumor tissue dissociation comprising: a) digesting tumor fragments in an enzyme solution; b) filtering the digestion solution through a cell strainer; c) further digesting the tumor fragments that remained in the strainer in a digestion solution; d) pooling the tumor digestions (pages 612-613 bridging paragraph and Fig. 1).
Regarding instant claims 13 and 20, it would have been obvious for a person having ordinary skill in the art to take the method of copending claims 1, 3, 10, 12-14, and 24 of ‘584 above comprising rapidly producing an expanded tumor reactive infiltrating lymphocyte population in a complete culture medium comprising IL-2 for use in adoptive cell therapy, wherein digestion is performed on the sample, and wherein one or more core biopsies or surgical resections from a solid tumor are digested without disaggregating the specimen, wherein culturing the TIL population in IL-2 comprising complete culture media for 5 weeks or less, wherein the TIL are harvested from the expanded TIL population, wherein the rapidly expanded TIL population harvested is administered to a subject, which would naturally produce expanded TILs with enriched tumor specificity – and modify the method to:
1) perform a core biopsy of a tumor wherein the tumor biopsy depth is between 20 and 30 mm, and wherein the tumor is 30 mm in view of Ullenhag; and
2) include a) a first round of digesting tumor fragments in an enzyme solution; b) filtering the digestion solution through a cell strainer to obtain excess non-digested tumor fragments; c) further digesting the excess digested tumor fragments that remained in the strainer in a digestion solution; and d) pooling the tumor digestions in view of Petit.
This is obvious because: 1) Ullenhag taught successful needle biopsies obtained with an 18 gauge needle that were 2 cm (20 mm) long and for a tumor that had a diameter of 30 mm, the 20 mm long core needle biopsy of the tumor would require a depth of 20 to 30 mm to obtain a tumor sample; and 2a) Simpson-Abelson taught following enzymatic digestion with DCH, solid material can remain in the cell strainer; 2b) Simpson-Abelson taught viable TILs are within tumor remnants (rTILs) that were effective; and 2c) Petit taught an effective method of tumor tissue dissociation comprising: a) enzymatically digesting tumor fragments in an enzyme solution; b) filtering the enzymatic digestion solution through a cell strainer; c) further digesting the tumor fragments that remained in the strainer in an enzymatic digestion solution; and d) pooling the tumor digestions.
There is a reasonable expectation of success because: 1a) Ullenhag taught a successful method of obtaining TIL from a tumor in a patient via a core needle biopsy, wherein needle biopsies were obtained with an 18 gauge needle that were 2 cm (20 mm) long; 1b) for a tumor that had a diameter of 30 mm, the 20 mm long core needle biopsy of the tumor would require a depth of 20 to 30 mm to obtain a tumor sample; 1c) Panelli taught TIL expansion in bulk tumor biopsies, wherein tumor cells, RBC, and TILs were present in a complete medium comprising IL-2, wherein CD4+ and CD8+ cells were obtained, wherein the TILs could recognize autologous tumor cells; 2a) Simpson-Abelson taught following enzymatic digestion with DCH, solid material can remain in the cell strainer and effective rTILs are known to be within the tumor. Thus, enzymatic digestion of the core sample then further enzymatic digestion of the excess tumor fragments that remained from the core biopsy, would allow more rTILs to be obtained from the core biopsy that could be pooled for expansion; 2b) Petit taught an effective method of tumor tissue dissociation comprising: a) enzymatically digesting tumor fragments in an enzyme solution; b) filtering the digestion solution through a cell strainer; c) further enzymatically digesting the tumor fragments that remained in the strainer in a digestion solution; and d) pooling the tumor digestions.
This would produce a method comprising rapidly producing an expanded tumor reactive infiltrating lymphocyte population in a culture medium comprising IL-2 for use in adoptive cell therapy, comprising:
obtaining a core needle biopsy aspirate of a solid tumor (instant claim 20) from a subject, wherein a core needle biopsy tissue sample of 2 cm (20 mm) from a 30 mm tumor is obtained from a subject which requires the needle to penetrate the tumor at a depth between about 20 and 30 mm to obtain the core biopsy tissue sample aspirate;
enzymatically digesting the core needle biopsy without previous disaggregation to a purified TIL population
filtering the enzymatic digestion solution through a cell strainer to obtain excess bulk digested core needle biopsy tumor fragments;
culturing and performing an expansion of the filtered TILs directly from a bulk, non-purified digested tumor sample from the subject in a complete culture medium comprising IL-2 in an amount effective to expand TILs with enriched tumor-reactivity;
contacting the excess bulk digested core needle biopsy tumor fragments that is non-purified from the filter with an enzymatic digestion solution to obtain additional TILs from the excess digested core needle biopsy that are a bulk, non-purified tumor digest that is digested without being disaggregated;
pooling the TILs from step (d) and (e) and culturing and performing an expansion of the TILs directly from a bulk, non-purified digested tumor sample from the subject in a complete culture medium comprising IL-2 in an amount effective to expand TILs with enriched tumor-reactivity for 5 weeks or less;
harvesting the expanded TIL population; and
administering the TIL to the subject for adoptive transfer for treatment of the tumor.
This meets the claim limitations of instant claim 13.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
The claims have been amended and new grounds of rejection are above.
Claims 1-2, 10-13, and 20-24 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 6-16, and 19-24 of copending Application No. 18/555,584 in view of US 20190276802 (Simpson-Abelson MR et al. effective filing date 11/17/2016 reference of record), Panelli MC et al. (J Immunol 2000 164 (1), 495–504 reference of record), Ullenhag et al. (Cancer Immunol Immunother. 2011 61(5):725–732.), and Petit V et al. (Laboratory Investigation 2013 93, 611–621), and Kamamoto D et al. (J Neurooncol 2018 139, 251–259 reference of record).
The claims of the copending ‘584, Simpson-Abelson, Panelli, Ullenhag, and Petit teach the limitations of claims 1-2, 10-13, and 20 for the reasons set forth above.
The claims of ‘584 did not teach: 1) the cancer is a solitary fibrous tumor, but this is obvious in view of Kamamoto.
Kamamoto taught CD8 was observed in TILs of 13/16 solitary fibrous tumors (abstract). Kamamoto taught diffuse PD-L1 staining coupled with no or sparse CD8 expression was significantly associated with a shorter time to treatment failure and showed a trend toward shorter metastasis free survival (abstract).
Regarding instant claims 21-24, it would have been obvious for a person having ordinary skill in the art to take the method of copending claims 1, 3, 10, 12-14, and 24 of ‘584, Simpson-Abelson, Panelli, Ullenhag, and Petit above
– and 1) expand TILs from solitary fibrous tumors for adoptive cell treatment of subjects with solitary fibrous tumors.
This is obvious because: 1) CD8 was observed in TILs of 13/16 solitary fibrous tumors; and lack of TILs in the tumor showed worst outcomes.
There is a reasonable expectation of success because: 1) TILs are present in solitary fibrous tumors and can be expanded; and 2) outcomes are poor when CD8 TILs are not in the tumor so increasing the TILs by adoptive transfer would be thought to be beneficial.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
The claims have been amended and new grounds of rejection are above.
Claims 1-2, 10-13, and 20-24 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-28 of copending Application No. 18/842,179 in view of US 20190276802 (Simpson-Abelson MR et al. effective filing date 11/17/2016 reference of record), Panelli MC et al. (J Immunol 2000 164 (1), 495–504 reference of record), Ullenhag et al. (Cancer Immunol Immunother. 2011 61(5):725–732.), and Petit V et al. (Laboratory Investigation 2013 93, 611–621).
Copending claims 1, 3, and 10 taught a method of rapidly producing an expanded tumor reactive infiltrating lymphocyte population in a complete culture medium comprising IL-2 in an amount to enrich tumor specificity, wherein digestion is performed on the sample, wherein the digestion is performed on a core sample without disaggregating the sample. Copending claims 6-7, 11-14, and 24-28 taught wherein one or more core biopsies are performed before digesting the sample, wherein the culture medium is a complete culture medium, wherein the TILs are cultured in IL-2 for 5 weeks or less, wherein the expanded TIL population is harvested, wherein the expanded TIL are used to treat a subject comprising administering to the subject the rapidly expanded TIL population, and wherein the tumor is a solitary fibrous tumor.
The claims of ‘179 are silent to: 1) the core sample being a core needle sample; 2) the depth of the needle biopsy; or 3) a method comprising more than one digestion of tumor fragments then pooling the tumor digestions, but this is obvious in view of Simpson-Abelson, Panelli, Ullenhag, and Petit.
Simpson-Abelson taught TILs may be cultured from enzymatic tumor digests and tumor fragments from sharp dissection (page 19, paragraph 503). Simpson-Abelson taught for enzymatic digestion of solid tumors; tumor specimens were resuspended in enzymatic digestion buffer followed by rotation (page 21, paragraph 521 and Fig. 2). Rotation of the enzymatic digest is a mechanical disruption of the tumor. Simpson-Abelson taught methods of delivering a therapeutically effective amount of an expanded number of tumor infiltrating lymphocytes obtained from tumor remnants to a patient in need thereof, for the treatment of a cancer (abstract). Simpson-Abelson taught using a MACS TDK enzymatic digest procedure, wherein the digest procedure caused poor yield and viability of rTILs was inferior to a procedure with DCH digest (page 34, paragraph 724). Simpson-Abelson taught following digestion with DCH solid material can remain in the cell strainer (page 34, paragraph 722). Simpson-Abelson taught during pre-REP of tumor fragments for TIL expansion, tumor-resident TILs emigrate as emigrating TILs (eTILs) and proliferate (page 34, paragraph 725). Simpson-Abelson taught viable TILs remaining in the tumor remnants (rTILs) following the pre-REP were investigated after digestion (page 34, paragraph 725), wherein enzymes are used (page 33, paragraph 719) and rTILs within digested bulk tumor are consistently phenotypically distinct from eTILs (page 34, paragraph 725), and rTILs in the digested tumor were identified to have desirable properties wherein A) rTILs are less terminally differentiated than eTILs (i.e., less likely to die) (pages 34-35, paragraph 728); B) rTIL have lower expression of “exhaustion markers” (LAG3 and TIM3) (page 35, paragraph 729). Simpson-Abelson taught as observed prior to REP, the eTILs and rTILs obtained post-REP were phenotypically distinct, wherein many of the phenotypic differences observed in the pre-REP were preserved during the REP, such as a reduction in LAG3 and TIM3 expression in the rTIL (page 35, paragraph 734 and FIG. 6B). Simpson-Abelson taught the eTIL from either the CD4+ or CD8+ population in melanoma and renal, colorectal, breast, and lung cancer tumors demonstrated an enhancement in the proliferative capacity upon co-culture with rTIL with anti-CD3 antibody when compared to eTIL alone (page 36, paragraph 744 and Fig 11). Simpson-Abelson taught the diversity of the TCRvβ repertoire is greater in the rTIL than in the eTIL (FIG. 9), wherein about 30-50% of the total CDR3 in the eTIL and rTIL are shared (FIG. 10), demonstrating that a large percentage of the total CDR3's are differentially expressed in the two populations (page 36, paragraph 741).
Panelli taught TIL expansion in bulk tumor biopsies, wherein tumor cells, RBC, and TILs were present in a 24-well plate with a complete culture medium comprising Iscove’s medium and 6000 IU/ml IL-2, wherein CD4+ and CD8+ cells were obtained (page 496, right column, third paragraph and Table 2 legend). Panelli taught biopsy expanded TILs could recognize autologous tumor cells (Fig. 1).
Ullenhag taught a successful method of obtaining tumor-infiltrating lymphocytes (TIL) from a tumor in a patient via a core needle biopsy (abstract). Ullenhag taught needle biopsies obtained with an 18 gauge needle that were 2 cm long (page 726, right column, first paragraph).
Petit taught an effective method of tumor tissue dissociation comprising: a) digesting tumor fragments in an enzyme solution; b) filtering the digestion solution through a cell strainer; c) further digesting the tumor fragments that remained in the strainer in a digestion solution; d) pooling the tumor digestions (pages 612-613 bridging paragraph and Fig. 1).
Regarding instant claims 1-2, 10-13, and 20-24, it would have been obvious for a person having ordinary skill in the art to take copending claims 1, 3, 6-7, 10-14, and 24-28 of ‘179 for a method of rapidly producing an expanded tumor reactive infiltrating lymphocyte population in a culture medium comprising IL-2 in an amount to enrich tumor specificity, wherein digestion is performed on the sample, wherein the digestion is performed on a core sample without disaggregating the sample, wherein one or more core biopsies are performed before digesting the sample, wherein the culture medium is a complete culture medium, wherein the TILs are cultured in IL-2 for 5 weeks or less, wherein the expanded TIL population is harvested, wherein the expanded TIL are used to treat a subject comprising administering to the subject the rapidly expanded TIL population, and wherein the tumor is a solitary fibrous tumor – and modify the method to include:
1) performing a core biopsy of a tumor wherein the tumor biopsy depth is between 20 and 30 mm, and wherein the tumor is 30 mm in view of Ullenhag; and
2) include a) a first round of digesting tumor fragments in an enzyme solution; b) filtering the digestion solution through a cell strainer to obtain excess non-digested tumor fragments; c) further digesting the excess digested tumor fragments that remained in the strainer in a digestion solution; and d) pooling the tumor digestions in view of Petit.
This is obvious because: 1) Ullenhag taught successful needle biopsies obtained with an 18 gauge needle that were 2 cm (20 mm) long and for a tumor that had a diameter of 30 mm, the 20 mm long core needle biopsy of the tumor would require a depth of 20 to 30 mm to obtain a tumor sample; and 2a) Simpson-Abelson taught following enzymatic digestion with DCH, solid material can remain in the cell strainer; 2b) Simpson-Abelson taught viable TILs are within tumor remnants (rTILs) that were effective; and 2c) Petit taught an effective method of tumor tissue dissociation comprising: a) enzymatically digesting tumor fragments in an enzyme solution; b) filtering the enzymatic digestion solution through a cell strainer; c) further digesting the tumor fragments that remained in the strainer in an enzymatic digestion solution; and d) pooling the tumor digestions.
There is a reasonable expectation of success because: 1a) Ullenhag taught a successful method of obtaining TIL from a tumor in a patient via a core needle biopsy, wherein needle biopsies were obtained with an 18 gauge needle that were 2 cm (20 mm) long; 1b) for a tumor that had a diameter of 30 mm, the 20 mm long core needle biopsy of the tumor would require a depth of 20 to 30 mm to obtain a tumor sample; 1c) Panelli taught TIL expansion in bulk tumor biopsies, wherein tumor cells, RBC, and TILs were present in a complete medium comprising IL-2, wherein CD4+ and CD8+ cells were obtained, wherein the TILs could recognize autologous tumor cells; 2a) Simpson-Abelson taught following enzymatic digestion with DCH, solid material can remain in the cell strainer and effective rTILs are known to be within the tumor. Thus, enzymatic digestion of the core sample then further enzymatic digestion of the excess tumor fragments that remained from the core biopsy, would allow more rTILs to be obtained from the core biopsy that could be pooled for expansion; 2b) Petit taught an effective method of tumor tissue dissociation comprising: a) enzymatically digesting tumor fragments in an enzyme solution; b) filtering the digestion solution through a cell strainer; c) further enzymatically digesting the tumor fragments that remained in the strainer in a digestion solution; and d) pooling the tumor digestions.
This would produce a method comprising rapidly producing an expanded tumor reactive infiltrating lymphocyte population in a complete culture medium comprising IL-2 for use in adoptive cell therapy, comprising:
obtaining a core needle biopsy aspirate of a solitary fibrous tumor (instant claims 20-24) from a subject, wherein a core needle biopsy tissue sample of 2 cm (20 mm) from a 30 mm tumor is obtained from a subject which requires the needle to penetrate the tumor at a depth between about 20 and 30 mm to obtain the core biopsy tissue sample aspirate;
enzymatically digesting the core needle biopsy without previous disaggregation to a purified TIL population
filtering the enzymatic digestion solution through a cell strainer to obtain excess bulk digested core needle biopsy tumor fragments;
culturing and performing an expansion of the filtered TILs directly from a bulk, non-purified digested tumor sample from the subject in a complete culture medium comprising IL-2 in an amount effective to expand TILs with enriched tumor-reactivity;
contacting the excess bulk digested core needle biopsy tumor fragments that is non-purified from the filter with an enzymatic digestion solution to obtain additional TILs from the excess digested core needle biopsy that are a bulk, non-purified tumor digest that is digested without being disaggregated;
pooling the TILs from step (d) and (e) and culturing and performing an expansion of the TILs directly from a bulk, non-purified digested tumor sample from the subject in a complete culture medium comprising IL-2 in an amount effective to expand TILs with enriched tumor-reactivity for 5 weeks or less (instant claim 11);
harvesting the expanded TIL population (instant claim 10); and
administering the TIL to the subject for adoptive transfer for treatment of the tumor (instant claim 12).
This method would naturally produce expanded TILs with enriched tumor specificity (instant claim 2). This meets the claim limitations of instant claims 1 and 13.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
The claims have been amended and new grounds of rejection are above.
Conclusion
No claims are allowable.
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/J.J.S./Examiner, Art Unit 1643
/Karen A. Canella/Primary Examiner, Art Unit 1643