DETAILED ACTION
Applicant’s amendment and response received on 3/3/26 has been entered. Claims 3-8, 10-13, 20-21, 24-25, ad 27-57 are now canceled. 1-2, 9, 14-19, 22-23, and 26 are now currently pending and under examination in this application based on the elected species of MAGE-A1- SEQ ID NO:7 as the species of antigen present in the dendritic cells, TRP-2 – SEQ ID NO:17 as the species of helper antigen, a compound of Formula I as the species of GITR/GITRL agonist. Note that independent claims 1, 17, and 22 have been amended to limit the GITR/GITRL agonist to the elected compound of Formula I.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . An action on the merits follows.
Those sections of Title 35, US code, not included in this action can be found in a previous office action.
Claim Objections
The objection to claims 2-3 because of grammatical errors where a definite or indefinite article is missing in front of the phrase “dendritic cell” or “cancer stem cell antigen” respectively, is withdrawn over in view of the amendment to claim 2 and the cancellation of claim 3.
Claims 1 and 22 are newly objected to because of the following informalities. Claims 1 and 22, as amended, now recite in part “MAGE-1peptide”. There is a space missing between MAGE-1 and peptide. Appropriate correction is required.
Claim Interpretation
The following claim interpretation has been applied to independent claims 1 and 17 and claims dependent thereupon. Claim 1 as amended recites, “administering to the subject …T cells that have been activated ex vivo with an antigen presenting cell” and as an alternative embodiment, “wherein the T cells have been further activated ex vivo with a GITR/GITRL agonist”. Claim 17 as amended continues to recite, “administering to the subject.. a sample of T-eff cells and/or cytotoxic T lymphocyte.. that have been activated ex vivo”. In both claim 1 and 17, the described ex vivo activation step(s) is/are not considered to be active method step(s) in the method, but rather something that has happened to the cells prior to their use in the instant methods. It is further noted that while these previously completed inactive method steps do impart a functional activity to the T cells or T-eff or CTL in that they are “activated”, the claims do not further define or limit the properties of the activated cells to any particular structural feature, phenotype, or functional activity. As such, based on the elected species of peptide, any activated T cells which has been exposed to the SEQ ID NO:7 or combination of SEQ ID NO:7 and SEQ ID NO:17 is considered to meet the claim limitation for activated T cells as recited in claims 1 and 17 and claims dependent therefrom.
Claim Rejections - 35 USC § 112
The rejection of previously pending claims 3-12, and 14-26 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, is withdrawn over the canceled claims, withdrawn over amended claims 9, 14-16, 22-23, and 26 in view of applicant’s amendments to the claims, and maintained over amended claims 17-19.
The applicant has amended claim 17 to add to the end of the claim the alternative, “or comprising administering the GITR/GITRL agonist in vivo to the subject, with T-eff cells and/or CTL..”. The applicant argues that this amendment overcomes the rejection of record. This is not agreed.
The rejection of record stated that claim 17 recites a method of treating cancer comprising “administering to the subject a therapeutically effective amount of a sample of T-eff cells and/or cytotoxic T lymphocytes that have been activated ex vivo, and enriched or expanded, wherein the T-eff cells and/or cytotoxic T cells are enriched or expanded by contacting the T-eff cells and/or CTL with a GITR/GITRL agonist with or without the presence of T-reg cells”. As written, it is unclear which steps in the method are active methods step which occur in vivo and which steps are steps which are not active method steps and have occurred in the past ex vivo. The claim clearly includes the active method step includes administering the T cells to a patient, i.e. in vivo, and also a kind of past-tense product by process limitation indicating that the T cells, prior administration to the patient, have been activated ex vivo. However, it is unclear where or when the T-eff cells and/or cytotoxic T cells are enriched or expanded by contact with GITR/GITRL agonist. In other words, is contact of the T cells with GITR/GITRL agonist an active method step in the method where the activated T cells contacted with the agonist prior to administration to the subject, an active method step where the GITR/GITRL agonist is also administered to the subject and the contacting with the T cells occurs in vivo in the subject, or whether the contacting of the T cells with the GITR/GITRL agonist is a past tense limitation that seeks to define the administered T cell by the process in which they were made ex vivo which is not an actual active method step in the method of treating as claimed. While applicant’s amendment to claim 17 now added an alternative limitation of in vivo administration of the GITR/GITRL agonist as an active step, the previous limitation stating in reference to the T-eff cells and/or cytotoxic T cells that they are, “enriched or expanded, wherein the T-eff cells and/or cytotoxic T cells are enriched or expanded by contacting the T-eff cells and/or CTL with a GITR/GITRL agonist with or without the presence of T-reg cells” has not been amended. This limitation remains unclear and indefinite since it is still unclear where or when the enrichment or expansion occurs. In other words, is the enrichment or expansion step of contact of the cells with GITR/GITRL agonist an active step that occurs in vitro/ex vivo, or is it a step that occurred in the past and thus not an active step in the method. Having and “or” clause added which provides an active step of in vivo administration of the GITR/GITRL agonist does not clarify the previous limitation for enrichment and expansion. As such, it is maintained that the metes and bounds of the claim cannot be determined. Claims 18-21 depend on claim 17 and thus are included in this rejection.
In the interests of compact prosecution, claims 17-21 have been interpreted to encompass an active step of contact of the T cells with GITR/GITRL agonist either ex vivo prior to administration or in vivo at the same time or post administration in the subject, or as part of the previously occurring preparation of the T cells that does not represent an active step in the instant method.
Applicant’s amendments to the claims has necessitated the following new grounds of rejection.
Claims 1-2, 9, 14-16, 22-23, and 26 are newly 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,
Independent claims 1 and 22 have been amended to recite, “wherein the antigen presenting cells have been pulsed with or modified to express MAGE-1peptide (SEQ ID NO:7)”. This limitation is confusing based on the recitation of the SEQ ID NO in parentheses. As written, it is not clear whether the MAGE-1 peptide is being limited to the peptide set forth in SEQ ID NO:7 or whether the “(SEQ ID NO:7)” just represents an example of a MAGE-1 peptide. It is suggested that applicant amended claims 1 and 22 to recite “MAGE-1 peptide as set forth in SEQ ID NO:7” in order to overcome this rejection. Claims 2, 9, 14-16, 23, and 26 depend on either claims 1 or 22 and thus are included in this rejection.
The rejection of previously pending claims 10-11, 17-20, 22-24 and 26 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, is withdrawn in view of applicant’s cancellation of or amendments to the claims.
The rejection of previously pending claims 10-11, 17-20, 22-24, and 26 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, for scope of enablement, in view of applicant’s cancellation of or amendments to the claims.
. Claim Rejections - 35 USC § 102
The rejection of claims 1-6 and 14-16 under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by WO 2019/126818 (27 June 2019), Wickham et al., with an effective filing date of 23 December 2017, as evidenced by Esparza t al. (2015) J. Neurooncol., Vol. 123, 448-457, is withdrawn over the canceled claims and further withdrawn over the amended claims which now recite that the T cells have been activated with antigen presenting cells pulsed or modified to express MAGE-1 peptide (SEQ ID NO:7) and with a helper antigen that is a polypeptide of TRP-2.
Claim Rejections - 35 USC § 103
The rejection of previously pending claims 1-9 and 14-16 under 35 U.S.C. 103 as being unpatentable over WO 2019/126818 (27 June 2019), Wickham et al., with an effective filing date of 23 December 2017, in view of Esparza t al. (2015) J. Neurooncol., Vol. 123, 448-457, and Phuphanich et al. (2013) Canc. Immunol. Immunother., Vol. 62, 125-135, is withdrawn over the canceled claims and maintained over amended claims 1-2, 9, and 14-16. Applicant’s arguments have been fully considered but have not been found persuasive in overcoming the rejection for reasons of record as discussed in detail below.
The applicant argues that the claims have been amended to include the limitation of previously pending claim 12 which was not rejected. However, this argument is not persuasive. Previously pending claim 12, which depended on claim 11, which depended on claim 10, recited and additional active step for the method of claim 1- see claim 10 which recited, the method of claim 1, further comprising contacting the T cells with GITR/GITRL. This limitation in claim 10 was an active limitation which read on contacting the T cells either in vitro prior to their administration to the subject or in vivo to the subject after or concurrently with the T cell administration. Claim 1 as now amended has added an alternative active step where GITR/GITRL is administered in vivo along with the activated T cells. Thus, in the alternative, the claims reads on 1) the administration of T cells which were previously activated with antigen presenting cells and expanded with GITR/GITRL in vitro, i.e. the activation and expansion are not active steps in the method, or 2) the GITR/GITRL is administered as an active step in vivo. The rejection of record still applies to the first alternative based on the claim interpretation which has been applied to claim 1. As set forth in the previous office action and reiterated above in the claim interpretation section, independent claim 1 has been interpreted as having a single active step of administering activated T cells to a subject for the treatment of cancer. While the claims recites that the T cells have been activated ex vivo by antigen presenting cells, or more specifically dendritic cells (claim 2), this is not an active step of the method and the only structural, phenotypic, or functional property recited for the T cells is that they are activated. As such, the teachings of Wickham et al., Esparza et al., and Phuphanich et al. apply and the rejection of record is maintained.
For clarity of prosecution, the teachings of Wickham et al., Esparza et al., and Phuphanich et al. and set forth in detail below.
Wickham et al. teaches methods of adoptive cell transfer (ACT) therapy for cancer where ex vivo activated tumor specific T cells are administering to a patient to treat cancer including melanoma and brain cancer (Wickham et al. pages 1, 14-15, and 21-22). Wickham et al. teaches that the T cells are activated ex vivo by contacting the cells with antigen-loaded antigen presenting cells (APCs) such as dendritic cells or artificial antigen presenting cells (aAPCs) expressing MHC-tumor antigen peptide complexes (Wickham et al., pages 1-2). Wickham et al. teaches that APCs comprise on the cell surface at least one or more specifically tumor antigens, where one of the one or more tumor specific antigens comprises a MAGE-A antigen peptide (Wickham et al., pages 3-4). Most specifically, Wickham et al. teaches that the MAGE-A antigen peptides include the MAGE-A1 peptide (161-169) EADPTGHSY (Wickham et al., page 98 and Table I). Note that this sequence is identical to instant SEQ ID NO:7. Further note that while Wickham et al. does not identify this MAGE-A1 peptide as a cancer stem cell antigen, MAGE-1/MAGE-A1 was known as in the prior art as being a cancer stem cell antigen. Esparza et al. for example teaches that MAGE-1 is a known cancer stem cell antigen (Esparza et al., page 453. Wickham et al. also teaches that the activated T cells include CD8+ T cells and CD4+ T cells (Wickham et al., page 5). Wickham et al. also teaches that the activated T cells can be administered in combination with other therapies such as chemotherapeutic drugs or cytokines, where the T cells and additional therapy are either co-administered, or administered sequentially (Wickham et al., page 357).
While Wickham et al. teaches that the APCs can be loaded with 2 different antigens, and further for the activation of both CD8+ T cells and CD8+ T cells, Wickham et al. differs from the instant invention by not specifically teaching to load the APCs with both the MAGE-1 peptide of SEQ ID NO:7 and the helper peptide of SEQ ID NO:17. However, Wickham et al. does teach that the second peptide is selected from a group with include the TRP-2 DR3 peptide (60-74) QCTEVRADTRPWSGP which is identical to SEQ ID NO:17 (Wickham et al., Table I). Thus, Wickham et al. teaches that the two peptides presented by the APCs for activating T cells can be selected from a list which includes both SEQ ID NO:7 and SEQ ID NO:17. Phuphanich et al. supplements the teachings of Wickham et al. by providing motivation to specifically combine peptides from MAGE1 and TRP-2 in dendritic cells for activating anti-tumor T cells in the treatment of brain tumors such as glioblastoma. Phuphanich et al. teaches antigen presenting cells and in particular dendritic cells can be pulsed with 6 specific tumor associated antigen peptides including a MAGE-1 peptide of instant SEQ ID NO:7 and a TRP-2 peptide, and can be used effectively to activate T cells ex vivo and in vivo with therapeutic activity against glioblastoma (Phuphanich et al., pages 125 and 127).
Therefore, based on teachings of Wickham et al. to combine more than 1, and more specifically at least two tumor antigen associated peptide epitopes, in order to activate T cells, and more specifically CD8+ T cells and CD4+ T cells, ex vivo where the tumor antigen associated peptide epitopes are selected from a group which includes both MAGE-1 (instant SEQ ID NO:7) and TRP-2 (instant SEQ ID NO:17), and the motivation to specifically load APCs with a MAGE-1 peptide of SEQ ID NO:7 and a TRP-2 peptide to activate anti-tumor T cells ex vivo taught by Phuphanich et al., it would have been prima facie obvious to the skilled artisan at the time of filing to activate T cells ex vivo using APCs including dendritic cells pulsed with SEQ ID NO:7 and SEQ ID NO:17 and to further administer the activated T cells to a subject to treat a cancer such as melanoma or glioblastoma et al. with a reasonable expectation of success.
The rejection of previously pending claims 1-6, 10-12, and 14-16 under 35 U.S.C. 103 as being unpatentable over WO 2019/126818 (27 June 2019), Wickham et al., with an effective filing date of 23 December 2017, in view of Esparza et al. (2015) J. Neurooncol., Vol. 123, 448-457, and US Patent Application Publication 2010/0297046 (2010), herein referred to as Schwartz, is withdrawn in view of applicant’s cancelation of the claims or amendments to the claims which now indicate that the T cells have been activated with APCs pulsed/modified to express both MAGE-1 and TRP-2 peptides.
Applicant’s amendments to the claims has necessitated the following new grounds of rejection.
Claims 1-2, 9, and 14-19 are newly rejected under 35 U.S.C. 103 as being unpatentable over WO 2019/126818 (27 June 2019), Wickham et al., with an effective filing date of 23 December 2017, in view of Esparza t al. (2015) J. Neurooncol., Vol. 123, 448-457, Phuphanich et al. (2013) Canc. Immunol. Immunother., Vol. 62, 125-135, and US Patent Application Publication 2010/0297046 (2010), herein referred to as Schwartz.
Note that claim 1 has been amended to include limitations previously found in canceled claims 7 and 12, thus necessitating the new grounds of rejection.
Independent claim 1 as amended has been interpreted as having a single active step of administering activated T cells to a subject for the treatment of cancer, or in the alternative as having the active steps of administering activated T cells and a GITR/GITRL agonist with the structure of compound 11702 to a subject for the treatment of cancer. While the claims recites that the T cells have been activated ex vivo by antigen presenting cells, or more specifically dendritic cells (claim 2), this is not an active step of the method and the only structural, phenotypic, or functional property recited for the T cells is that they are activated.
Wickham et al. teaches methods of adoptive cell transfer (ACT) therapy for cancer where ex vivo activated tumor specific T cells are administering to a patient to treat cancer including melanoma and brain cancer (Wickham et al. pages 1, 14-15, and 21-22). Wickham et al. teaches that the T cells are activated ex vivo by contacting the cells with antigen-loaded antigen presenting cells (APCs) such as dendritic cells or artificial antigen presenting cells (aAPCs) expressing MHC-tumor antigen peptide complexes (Wickham et al., pages 1-2). Wickham et al. teaches that APCs comprise on the cell surface at least one or more specifically tumor antigens, where one of the one or more tumor specific antigens comprises a MAGE-A antigen peptide (Wickham et al., pages 3-4). Most specifically, Wickham et al. teaches that the MAGE-A antigen peptides include the MAGE-A1 peptide (161-169) EADPTGHSY (Wickham et al., page 98 and Table I). Note that this sequence is identical to instant SEQ ID NO:7. Further note that while Wickham et al. does not identify this MAGE-A1 peptide as a cancer stem cell antigen, MAGE-1/MAGE-A1 was known as in the prior art as being a cancer stem cell antigen. Esparza et al. for example teaches that MAGE-1 is a known cancer stem cell antigen (Esparza et al., page 453. Wickham et al. also teaches that the activated T cells include CD8+ T cells and CD4+ T cells (Wickham et al., page 5). Wickham et al. also teaches that the activated T cells can be administered in combination with other therapies such as chemotherapeutic drugs or cytokines, where the T cells and additional therapy are either co-administered, or administered sequentially (Wickham et al., page 357).
While Wickham et al. teaches that the APCs can be loaded with 2 different antigens, and further for the activation of both CD8+ T cells and CD8+ T cells, Wickham et al. differs from the instant invention by not specifically teaching to load the APCs with both the MAGE-1 peptide of SEQ ID NO:7 and the helper peptide of SEQ ID NO:17. However, Wickham et al. does teach that the second peptide is selected from a group with include the TRP-2 DR3 peptide (60-74) QCTEVRADTRPWSGP which is identical to SEQ ID NO:17 (Wickham et al., Table I). Thus, Wickham et al. teaches that the two peptides presented by the APCs for activating T cells can be selected from a list which includes both SEQ ID NO:7 and SEQ ID NO:17. Phuphanich et al. supplements the teachings of Wickham et al. by providing motivation to specifically combine peptides from MAGE1 and TRP-2 in dendritic cells for activating anti-tumor T cells in the treatment of brain tumors such as glioblastoma. Phuphanich et al. teaches antigen presenting cells and in particular dendritic cells can be pulsed with 6 specific tumor associated antigen peptides including a MAGE-1 peptide of instant SEQ ID NO:7 and a TRP-2 peptide, and can be used effectively to activate T cells ex vivo and in vivo with therapeutic activity against glioblastoma (Phuphanich et al., pages 125 and 127).
Therefore, based on teachings of Wickham et al. to combine more than 1, and more specifically at least two tumor antigen associated peptide epitopes, in order to activate T cells, and more specifically CD8+ T cells and CD4+ T cells, ex vivo where the tumor antigen associated peptide epitopes are selected from a group which includes both MAGE-1 (instant SEQ ID NO:7) and TRP-2 (instant SEQ ID NO:17), and the motivation to specifically load APCs with a MAGE-1 peptide of SEQ ID NO:7 and a TRP-2 peptide to activate anti-tumor T cells ex vivo taught by Phuphanich et al., it would have been prima facie obvious to the skilled artisan at the time of filing to activate T cells ex vivo using APCs including dendritic cells pulsed with SEQ ID NO:7 and SEQ ID NO:17 and to further administer the activated T cells to a subject to treat a cancer such as melanoma or glioblastoma et al. with a reasonable expectation of success.
Wickham et al., while teaching that other therapies can be administered in combination with the activated T cells for the treatment of a cancer such as melanoma, Wickham et al. does not teach that the additional therapy is a compound of Formula I, and more specifically the compound depicted in claim 1 and referred to as compound 11702 in the specification. Schwartz et al. supplements Wickham et al. by teaching a compound of Formula I with anti-cancer properties, and more specifically a compound of Formula I which is identical to the compound depicted in instant claim 1 (Schwartz et al., Figure 21A and claims 1 and 49).
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Schwartz et al. further teaches methods for treating skin diseases or disorders including skin cancer and melanoma by administering the compound to the subject (Schwartz et al., pages 5 and 29, and claims 1, 38, and 49).
Therefore, in view of teachings of Wickham et al. to combine the administration of activated T cells which have been activated ex vivo with APCs presenting the MAGE-1 peptide of SEQ ID NO:7 with an anti-cancer therapeutic drug, and the teachings of Schwartz et al. that the compound set forth in claim 12 can be used to treat diseases including skin cancer and melanoma, it would have been prima facie obvious to the skilled artisan at the time of filing to administer both the activated T cells taught by Wickham et al. in view of Esparza et al. and the compound depicted in instant claim 12 as taught by Schwartz et al. with a reasonable expectation of success in treating a cancer such a melanoma.
No claims are allowed.
Applicant's amendment necessitated the new ground(s) 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 from the examiner should be directed to Anne Marie S. Wehbé, Ph.D., whose telephone number is (571) 272-0737. If the examiner is not available, the examiner’s supervisor, Maria Leavitt, can be reached at (571) 272-1085. For all official communications, the technology center fax number is (571) 273-8300. Please note that all official communications and responses sent by fax must be directed to the technology center fax number. For informal, non-official communications only, the examiner’s direct fax number is (571) 273-0737. For any inquiry of a general nature, please call (571) 272-0547.
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Dr. A.M.S. Wehbé
/ANNE MARIE S WEHBE/Primary Examiner, Art Unit 1634
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