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 .
Claims 1-4, 7-9, 14, 16-18, 20, 37, 46-49, 51, 54, 58-60, 66-70, 73, 74, 78-80, 85, and 88 are pending and currently under consideration.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1-4, 7, 16, 37, 46-48, 51, 54, 58, 73, 74, 78, 85, and 88 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Frank et al (US 2018/0228841 A1; 8/16/18; 8/13/24 IDS).
Frank et al teaches a method comprising expanding tumor infiltrating lymphocytes (TILs) comprising (i) obtaining a first population of TILs from a resected tumor sample a patient, (ii) performing a first expansion by culturing the first population of TILs in a culture medium comprising IL-2 to produce a second population of TILs, and (iii) performing a second expansion by supplementing the culture medium of the second population of TILs with additional IL-2, anti-CD3 antibody OKT-3, and antigen presenting cells (APCs) to produce a third population of TILs ([0012], in particular). Frank et al further teaches T cells express CD3 and are stimulated by the anti-CD3 antibody OKT-3 ([0185] and [0248], in particular). Frank et al further teaches said method wherein, after step (iii), the cells are removed/harvested from culture and cryopreserved in storage medium ([0015], in particular). Frank et al further teaches said method wherein the resected tumor sample is cryopreserved before or after fragmentation/disaggregating the resected tumor sample and the TILs are obtained from the fragmented/disaggregated sample ([0217]-[0218], in particular). Frank et al further teaches said method wherein cells of the sample are cryopreserved and thawed prior to step (i) ([0081]-[0082], in particular). Frank et al further teaches said method wherein thawed cells are resuspended in complete media and washed one or more times ([0297], in particular). Frank et al further teaches said method wherein the cryopreservation uses the cryopreservant DMSO ([0296], in particular), that gets washed/removed when washing one or more times. Frank et al further teaches said method wherein the tumor sample is “optionally” cryopreserved ([0211], in particular) and, therefore, includes methods wherein the tumor sample is not cryopreserved. Frank et al further teaches said method wherein the resected tumor sample is first processed/fragmented before or after cryropreservation ([0214]-[0220], in particular). Frank et al further teaches said method wherein the first population of TILs are transduced with a chimeric antigen receptor (CAR) ([0025], in particular). Frank et al further teaches said method wherein the tumor is NSCLC ([0061], in particular). Frank et al further teaches said method wherein culture medium has 1,000, 2,000, or 3,000 IU/ML IL-2 ([0246], in particular). Frank et al further teaches said method wherein the first population of TILs expanded in the second expansion comprise 1x106 TILs ([0234], in particular). Frank et al further teaches said method wherein the second expansion occurs in medium with 3000 IU/mL IL-2 ([0234], in particular). Frank et al further teaches TILs can be expanded with one or more antigens, optionally in the presence of a T-cell growth factor such as 300 IU/mL IL-2 or IL-15 ([0236], in particular). Frank et al does not teach a second cell culture medium comprising FBS. Frank et al further teaches said method wherein the APCs are PBMCs ([0330], in particular) that are obtained by leukapheresis ([0836], in particular). Frank et al further teaches said method wherein the second expansion comprises a rapid expansion protocol (REP) and can be rapidly expanded with antigens ([0236], in particular), which appears to be the same as a “static (first) expansion followed by a dynamic expansion.” Frank et al further teaches said method wherein the first (“static”) expansion is no more than 14 days ([0401], in particular). Frank et al further teaches said method wherein the second (“dynamic”) expansion is performed for 14 days ([0012], in particular). Frank et al further teaches the REP culture comprising rhIL-2 ([0453], in particular), which comprises HSA ([0552], in particular). Frank et al further teaches said method wherein cell expansion occurs in a 3 L bag or a bag from 300 ml to 10 L ([0293], in particular). Frank et al further teaches said method wherein the TILs are cryopreserved in DMSO following the second expansion ([0256], in particular). Frank et al further teaches said method wherein potency of the harvested TILs is measured by interferon (including IFNg) release ([0169], in particular) and TILs can be evaluated by culturing the TILs with OKT3 or autologous tumor digest and quantifying interferon release ([0303], in particular). Frank et al further teaches said method wherein the harvested TILs are therapeutically administered to subjects with cancer ([0046], in particular) and are administered at a dose from about 2.3x1010 to about 13.7x1010 TILs ([0270], in particular).
Claim Rejections - 35 USC § 103
Claims 1-4, 7-9, 14, 16-18, 20, 37, 46-49, 51-54, 58, 59, 73, 78, 85, and 88 are rejected under 35 U.S.C. 103(a) as being unpatentable over Benson et al (WO 2021/173964 A1; 9/2/21).
Benson et al teaches methods of activating and/or expanding lymphocytes, such as T cell lymphocytes (Abstract, in particular). Benson et al further teaches TILs are obtained by mechanically cutting surgically resected tumor samples into small pieces ([0003], in particular). Benson et al further teaches TILs are obtained by mechanically dissociating (such as using GentleMACS) tumor samples in enzyme media, and wherein the mechanical dissociation is performed for approximately one minute and repeating the one minute mechanical dissociation one or two additional times if large pieces of tissue are present ([0148], in particular). Benson et al further teaches the tumor can be from a cancer such as NSCLC ([0106], in particular). Benson et al further teaches TILs are activated and expanded through a multi-step process that includes at least one rapid expansion protocol (REP) step (same as “dynamic expansion”) that is preceded by a separate pre-REP step (same as “static expansion”) ([0151], in particular). The multi-step method of Benson of activating and expanding TILs is “shortened” in duration, comprising a first expansion/”static”/pre-REP step that last 3-14 days ([0160]) and a second expansion/”dynamic”/REP that can be 7-14 days or longer ([0162]). Benson et al further teaches the first expansion/”static”/pre-REP step comprises culturing the TILs in medium comprising a T-cell stimulating cytokine such as IL-2, IL-7, IL-15, IL-21, and combinations thereof ([0152], in particular) until several million TILs are obtained ([0157], in particular). Benson et al further teaches the second expansion/”dynamic”/REP step comprises culturing TILs from the first expansion in medium comprising T-cell stimulating cytokines such as IL-2, IL-7, IL-15, IL-21, and combinations thereof, a CD3 agonist or CD3 agonist antibody OKT3 , and feeder cells such as PBMC or APCs (including APCs that are PBMCs; see [0164]) to produce a second population of TILS ([0162]-[0164], in particular). Benson et al teaches using culture medium comprising 300-6000 U/mL of IL-2 and 10-7000 U/mL of IL-7 and/or IL-21 to stimulate T cells ([085], in particular). Benson et al further teaches harvesting the TILs after the second expansion ([0177], in particular). Benson et al further teaches changing the culture medium of the first and second steps every one to six days ([088]-[089], in particular). Benson et al further teaches the TILs transduced to express a chimeric antigen receptor (CAR) comprising an extracellular domain that targets tumor cells and an intracellular signaling domain ([00249], in particular), including CAR comprising an intracellular signaling domain that is a costimulatory domain such as 4-1BB, CD28, CD40, MyD88, or CD70 domain and that such CARs are well-known in the art ([02050], in particular). Benson et al further teaches tumor samples are “optionally” cryopreserved after obtaining the sample ([0149], in particular). Benson et al further teaches performing cryopreservation before or after fragmentation of the tumor sample ([0146], in particular). Benson et al further teaches expanded TILs of Benson et al can be used immediately or cryopreserved for later use ([0690], in particular). Benson et al further teaches washing TILs that have been previously cryopreserved prior to placing the TILs into culture medium ([0830], in particular). Benson et al further teaches DMSO as cropreservant used to freeze TILs ([00690], in particular). Benson et al further teaches the expansions are performed in bags, including 100ml to 10L bags, including 3L bags ([0175], in particular). Benson et al further teaches initial populations of TILs ranging from 100 to 5x107 TILs and the methods of Benson et al expand the TILs at least 1500 fold ([0226], in particular). Benson et al further teaches methods of treating a subject with cancer comprising administering from about 1x109 to 2x1011 of the expanded TILs ([0701]-[0704], in particular). Benson et al further teaches methods of determining potency of the TILs expanded and activated by Benson et al by detecting IFNg secretion in response to co-culturing the TILs with OKT3 or autologous tumor digest ([0237], in particular).
While Benson et al discloses methods that overlap with the claims (such as overlapping reagents, overlapping amounts, and overlapping times) Benson et al does not demonstrate the claimed method. However, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a method of Benson et al comprising activating and expanding TILs from a subject of Benson et al with cancer (such as NSCLC; see [0106]) by (a) obtaining a resected tumor sample from the subject that has been processed by mechanically cutting surgically resected tumor samples into small pieces or by mechanically dissociating (such as using GentleMACS) tumor samples in enzyme media in any bag(s) of Benson et al (100ml to 10L; including a 3L bag) as taught by Benson et al (([0003], [00148], and [0175], in particular), (b) performing a first expansion/”static”/pre-REP step of Benson et al that lasts 3-14 days ([0160]) by culturing the processed resected tumor product comprising TILs in a cell culture medium comprising IL-2 and (optionally IL-7, IL-15, and/or IL-21) of Benson et al ([0152], in particular) at concentrations taught by Benson et al ([085], in particular) until several million TILs are obtained ([0157]), (c) performing a second expansion/”dynamic”/REP of Benson et al that can be 7-14 days ([0162]) by culturing the TILs from the first expansion/”static”/pre-REP step in a cell culture medium of Benson et al in any bag(s) of Benson et al (100ml to 10L; including a 3L bag) comprising IL-2 and (optionally IL-7, IL-15, and/or IL-21) at concentrations taught by Benson et al ([085], in particular), a CD3 agonist or CD3 agonist antibody OKT3 , and feeder cells such as PBMC or APCs (including APCs that are PBMCs; see [0164]) to produce a second population of TILS ([0162]-[0164] and [0175], in particular), (d) harvesting the TILs after the second expansion (as taught by Benson et al at [0177], in particular) and treating a subject with cancer by administering to the subject a therapeutic population comprising from about 1x109 to 2x1011 of the harvested expanded TILs (as taught by Benson et al [0701]-[0704], in particular).
In particular regards to claims 2-4, 7, and 37, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform said method wherein the resected tumor sample and/or TILs are optionally (see claim 7) cryopreserved with DMSO and then thawed and washed after cryopreservation (as taught by [0146], [0149], [0690], and [0830] Benson et al) at any point in order to (i) stop and continue the method at any time point and (ii) wash away cryopreservant of Benson et al that is known by those skilled in the art to be toxic to thawed cells.
In particular regards to instant claims 8-9, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the method wherein the fragmentation/disaggregation is performed by any method that comprises mechanical disaggregation that involves any amount of pressure applied any amount of times for a duration that includes 1-3 minutes because Benson et al teaches TILs are obtained by mechanically cutting (which involves pressure applied numerous times) surgically resected tumors into small pieces ([0003], in particular) and that TILs are obtained by mechanically dissociating (such as using GentleMACS – which involves pressure) tumors in enzyme media, and wherein the mechanical dissociation is performed for approximately one minute and repeating the one minute mechanical dissociation one or two additional times if large pieces of tissue are present ([0148], in particular).
In particular regards to instant claims 14, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the method wherein the TILS are TILs of Benson et al that are transduced to express a CAR wherein the CAR is a CAR of Benson et al that targets tumors and comprises an intracellular co-stimulatory domain because the TILs of Benson et al are to treat cancer ([0701]-[0704], in particular) and Benson et al teaches TILs expressing a chimeric antigen receptor (CAR) comprising an extracellular domain that targets tumor cells and an intracellular signaling domain ([0249], in particular), including CAR comprising an intracellular signaling domain that is a costimulatory domain such as 4-1BB, CD28, CD40, MyD88, or CD70 domain and that such CARs are well-known in the art ([0250], in particular).
In particular regards to claim 78, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform said method wherein the potency of the harvested TILs are assessed prior to administering the TILs to the subject by detecting IFNg secretion in response to co-culturing the TILs with OKT3 or autologous tumor digest because one would want to only administer potent TILs and Benson et al teaches assessing TIL potency by detecting IFNg secretion in response to co-culturing the TILs with OKT3 or autologous tumor digest ([0237], in particular).
Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Claim Rejections - 35 USC § 103
Claim(s) 1-4, 7-9, 14, 16-18, 20, 37, 46-49, 51-54, 58, 59, 66-69, 73, 78, 85, and 88 is/are rejected under 35 U.S.C. 103 as being unpatentable over Benson et al (WO 2021/173964 A1; 9/2/21) as applied to claims 1-4, 7-9, 14, 16-18, 20, 37, 46-49, 51-54, 58, 59, 73, 78, 85, and 88 above, and further in view of Langer et al (WO 2020/172202 A1; 8/27/20).
Teachings of Benson et al are discussed above.
While Benson et al teaches changing culture medium ([0701]-[0704], in particular), Benson et al does not specifically teach culture medium is changed (removing spent cell culture medium while simultaneously adding fresh culture medium in equal parts and maintain the same volume) as recited by instant claims 66-69. However, these deficiencies are made up in the teachings of Langer et al.
Langer et al teaches TIL culture medium in culture bags similar to Benson et al is changed by perfusion at rates such as 0.01-2.0 L/min or 290-1160 mL/day ([0220]-[0221], in particular).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the method rendered obvious by Benson et al wherein the culture medium is changed by perfusion (removing spent cell culture medium while simultaneously adding fresh culture medium in equal parts and maintain the same volume) as taught by Langer et al during the first and second steps every one to six days, at increasing amounts (including changing a six time points wherein the fresh medium at the fourth time point is any amount from about 0.6 to about 1 L/day, the fresh medium at the fifth time point is any amount from about 1.4 to about 1.8 L/day, and the fresh medium at the sixth time point is any amount from about 3 to about 3.4 L/day) because Benson et al teaches changing the culture medium of the first and second steps every one to six days ([088]-[089], in particular) and because the cultures expand over time to larger populations requiring more nutrients and removal of spent culture medium by mor cells.
Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Claim Rejections - 35 USC § 103
Claim(s) 1-4, 7, 16, 37, 46-48, 51, 54, 58, 70, 73, 74, 78, 85, and 88 is/are rejected under 35 U.S.C. 103 as being unpatentable over Frank et al (US 2018/0228841 A1; 8/16/18; 8/13/24 IDS) as applied to claims 1-4, 7, 16, 37, 46-48, 51, 54, 58, 73, 74, 78, 85, and 88 above, and further in view of Whiteside et al (Cancer Immunology Immunotherapy, 1994, 39: 15-21).
Teachings of Frank et al are discussed above.
While Frank et al teaches administering about 2.3x1010 to about 13.7x1010 of the harvested TILs ([0270], in particular), Frank et al does not specifically teach harvesting is performed when there is at least 5x109 CD3+ total viable cells or at least 8.5x109 CD3+ total viable cells. However, these deficiencies are made up in the teachings of Whiteside et al.
Whiteside et al teaches TILs are mainly CD3+TCRa/b+ cells (left column on page 15, in particular) and TILs of the method of Frank et al predictably express CD3 because CD3 agonist is used by Frank et al to stimulate the cells.
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the method of Frank et al wherein harvesting is performed when there is at least 2.3x1010 to about 13.7x1010 viable TILs (which would be at least 5x109 CD3+ total viable cells or at least 8.5x109 CD3+ total viable cells because Whiteside et al teaches TILs are mainly CD3+TCRa/b+ cells (left column on page 15, in particular) and TILs of the method of Frank et al predictably express CD3 because CD3 agonist is used by Frank et al to stimulate the cells) because Frank et al teaches administering 2.3x1010 to about 13.7x1010 TILs and the TILs should be viable to therapeutically attack tumor cells. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Claim Rejections - 35 USC § 103
Claim(s) 1-4, 7-9, 14, 16-18, 20, 37, 46-49, 51-54, 58, 59, 70, 73, 78, 85, and 88 is/are rejected under 35 U.S.C. 103 as being unpatentable over Benson et al (WO 2021/173964 A1; 9/2/21) as applied to claims 1-4, 7-9, 14, 16-18, 20, 37, 46-49, 51-54, 58, 59, 73, 78, 85, and 88 above, and further in view of Whiteside et al (Cancer Immunology Immunotherapy, 1994, 39: 15-21).
Teachings of Benson et al are discussed above.
While Benson et al teaches administering 1x109 to 2x1011 of the harvested TILs ([0701]-[0704], in particular), Benson et al does not specifically teach harvesting is performed when there is at least 5x109 CD3+ total viable cells or at least 8.5x109 CD3+ total viable cells. However, these deficiencies are made up in the teachings of Whiteside et al.
Whiteside et al teaches TILs are mainly CD3+TCRa/b+ cells (left column on page 15, in particular) and TILs of the method of Benson et al predictably express CD3 because CD3 agonist is used by Benson et al to stimulate the cells.
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform methods rendered obvious by Benson et al wherein harvesting is performed when there is at least 1x109 to 2x1011 viable TILs (which would be at least 5x109 CD3+ total viable cells or at least 8.5x109 CD3+ total viable cells because Whiteside et al teaches TILs are mainly CD3+TCRa/b+ cells (left column on page 15, in particular) and TILs of the method of Benson et al predictably express CD3 because CD3 agonist is used by Benson et al to stimulate the cells) because Benson et al teaches administering 1x109 to 2x1011 TILs and the TILs should be viable to therapeutically attack tumor cells. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Claim Rejections - 35 USC § 103
Claim(s) 1-4, 7-9, 14, 16-18, 20, 37, 46-49, 51-54, 58, 59, 73, 78-80, 85, and 88 is/are rejected under 35 U.S.C. 103 as being unpatentable over Benson et al (WO 2021/173964 A1; 9/2/21) as applied to claims 1-4, 7-9, 14, 16-18, 20, 37, 46-49, 51-54, 58, 59, 73, 78, 85, and 88 above, and further in view of Ben-Avi et al (Cancer Immunotherapy, 2018, 67: 1221-1230) and Yoshino et al (Lung Cancer, 1993, 10, (1-2), pages 13-19).
Teachings of Benson et al are discussed above. Benson et al teaches that, in addition to using anti-CD3 agonists to stimulate and expand the TILs, Benson et al teaches using anti-CD2 agonists to stimulate and expand the TILs ([015] and [0101], in particular).
While Benson et al teaches potency of the harvested TILs are assessed prior to administering the TILs to the subject by detecting IFNg secretion in response to co-culturing the TILs with OKT3 or autologous tumor digest ([0237], in particular), Benson et al does not specifically teach detecting TILs that express IFNg in the activated TILs. However, these deficiencies are made up in the teachings of Ben-Avi et al and Yoshido et al.
Ben-Avi et al teaches percent IFNg positivity, determined by flow cytometry gated on CD8+ TILs, as a measure of potency of TILs that mirrors IFNg secretion of the cells (Figure 2, in particular).
The abstract of Yoshido et al teaches TILs exhibit higher values of CD3+ (p ˂0.05), CD8+ (p ˂0.05), and CD2+ CD3+ (p ˂0.01) as compared to those in peripheral blood lymphocytes (PBL).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform methods rendered obvious by Benson et al the TILs are further cultured with anti-CD2 agonists to stimulate and expand the TILs and wherein, instead of determining potency by measuring IFNg secretion, potency is determined by determining percent IFNg positivity determined by flow cytometry gated on viable CD2+ TILs because Ben-Avi et al teaches percent IFNg positivity determined by flow cytometry gated on positivity of a TIL marker as a measure of potency of TILs that mirrors IFNg secretion of the cells (Figure 2, in particular), CD2 is a TIL marker (see Abstract of Yoshida et al), TILs stimulated with an anti-CD2 agonist of Benson et al predictably express CD2, and TILs need to be viable to attack tumors. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Conclusion
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