DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s amendment filed on 05/26/2026 has been entered.
Amended claims 1-4, 6-7 and 9-20 are pending in the present application.
Applicant elected previously without traverse of Group I, which is drawn to a method for treating a malignancy in a subject, the method comprising contacting a composition to enrich for TPEX cells and/or TOX+TEFF cells to a plurality of T cells to enhance anti-tumor activity of the plurality of T cells to treat the malignancy.
Applicant also elected previously the following species: (i) a decoy-resistant IL-18 (DR-18); and (ii) contacting the composition expands IFNγ+TOX+TEFF cells and promotes tumor-specific immunity.
Claims 11-20 were withdrawn from further consideration because they are directed to a non-elected invention. Additionally, claim 4 was also withdrawn previously from further consideration because it is directed to a non-elected species.
Accordingly, amended claims 1-3, 6-7 and 9-10 are examined on the merits herein with the above elected species.
Response to Amendment
1. The rejection under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, for Lack of Written Description was withdrawn in light of currently amended independent claim 1.
2. The rejection under 35 U.S.C. 102(a)(a) as being anticipated by Ring et al (US 2019/0070262) was withdrawn in light of currently amended independent claim 1, particularly with at least the new limitation “at a time when TOX+ TEFF cells are not outnumbered by malignant cells in the bone marrow”.
3. All 103 rejections that are based over Ring et al (US 2019/0070262) as set forth in the Non-Final Office Action dated 02/26/2026 were also withdrawn in light of currently amended independent claim 1, particularly with at least the new limitation “wherein the ratio of TOX+ TEFF_3 cluster cells to malignant cells in the bone marrow increases following the administering”.
4. The provisional nonstatutory double patenting as being unpatentable over claims 21-37 of copending Application No. 18/062.522 (reference application) was withdrawn in light of currently amended independent claim 1 and upon further considerations.
Claim Objections
Claim 1 is objected to because of the terms “TEFF” and “TPEX”, which should be conventionally written as - - TEFF - - and - - TPEX - -, respectively. Claim 1 is also objected because of the phase “a TOX+ TEFF cells” which is grammatically incorrect.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Amended claims 1-3, 6-7 and 9-10 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for:
A method for treating a hematological malignancy in a subject that received an allogeneic bone marrow transplant, the method comprises:
administering a decoy-resistant IL-18 (DR-18) to the subject at day 7 post-transplant for 4-5 weeks at a frequency of twice a week to the subject to enrich for TPEX cells and/or TOX+ CD8 TEFF cells, wherein the ratio of TOX+ CD8 TEFF_3 cluster cells to malignant cells increases in the bone marrow of the subject following the administering; and thereby treating the hematological malignancy in the subject;
does not reasonably provide enablement for any other method for treating a malignancy in a subject as claimed broadly. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
The instant specification is not enabled for a method for treating a malignancy in a subject as claimed broadly for the reasons discussed below.
The breadth of the claims
The instant claims encompass a method for treating any malignancy in a subject, the method comprising administering DR-8 to the subject at any time as long as at a time when TOX+TEFF cells are not outnumbered by malignant cells in the bone marrow to enrich for TPEX cells and/or TOX+TEFF cells (TOX+ CD8 TEFF and TOX+ CD4 TEFF cells) for any period of time and/or at any frequency, wherein the ratio of TOX+TEFF_3 cluster cells (TOX+ CD8 TEFF_3 cluster cells and TOX+ CD4 TEFF_3 cluster cells) to malignant cells in the bone marrow increases following the administering, thereby treating the malignancy in the subject that received any stem cell transplant (e.g., a mesenchymal stem cell transplant, a neural stem cell transplant, a skeletal stem cell transplant).
2. The state and the unpredictability of the prior art
Before the effective filing date of the present application (02/23/2022), virtually nothing was known about the use of a decoy-resistant IL-18 (DR-18) to enrich TPEX cells (progenitors exhausted CD8+T cells) and/or TOX+TEFF cells (exhausted CD4 and/or CD8 T cells) to treat any malignancy in a subject that received any stem cell transplant, let alone administering the DR-18 to the subject at a time when TOX+TEFF cells are not outnumbered by malignant cells in the bone marrow and wherein the ratio of TOX+TEFF_3 cluster cells to the malignant cells increases following the administering as evidenced at least by the teachings of Khan et al (Nature 571:211-218, 2019; IDS), Scott et al (Nature 571:270-274, 2019; IDS), Ring et al (US 2019/0070262) and Nakamura et al (Immunology & Cell Biology 98:434-436, 2020). Khan et al stated “Exhausted CD8+ T (Tex) cells in chronic infections and cancer have limited effector function, high co-expression of inhibitory receptors and extensive transcriptional changes compared with effector (Teff) or memory (Tmem) CD8+T cells” (first sentence of Abstract). Scott et al also stated “Here we identify the nuclear factor TOX as a crucial regulator of the differentiation of tumor-specific T (TST) cells. We show that TOX is highly expressed in dysfunctional TST cells from tumours and in exhausted T cells during chronic viral infection….Ectopic expression of TOX in effector T cells in vitro induced a transcriptional program associated with T cell exhaustion” (Abstract). Furthermore, please note that the physiological art is recognized as unpredictable (MPEP 2164.03).
The amount of direction or guidance provided
Apart from disclosing a murine model of myeloma, in which myeloma (MM)-bearing recipient mice were also transplanted with an allogeneic bone marrow transplant and treated with decoy-resistant IL-18 (DR-18) from Day 7 after the bone marrow transplant for 4-5 weeks at a frequency of twice a week; and all DR-18 treated mice controlled myeloma at 6 weeks post-transplant and this was associated with increased frequency of IFNγ+CD8 T-cells, as well as an expansion of precursor exhausted (TPEX) and TOX+TEFF cells (or TOX+TIM-3+TEX T cells; specification at page 17, lines 12-14), including an increase in TOX+TEFF_3 cluster cells with high expression of Maf and cytotoxic genes including perforin (specification at page 20, line 21 continues to line 7 on page 21) compared to PBS-treated mice (see at least sections titled “A decoy resistant IL-18 expands IFNγ-secreting TOX+ TEFF cells and promotes myeloma control” and “Myeloma model and stem cell transplantation” at page 19 and 23, respectively; FIGs. 3A-B and 10A-B); the instant specification fails to provide sufficient guidance for an ordinary skilled artisan at least on how to treat any other non-hematological malignancy in a subject that received any other stem cell transplant, along with the administration of DR-18 at any other time as long as at a time when TOX+TEFF cells are not outnumbered by malignant cells in the bone marrow of the subject and particularly wherein the ratio of TOX+TEFF_3 cluster cells to malignant cell in the bone marrow increases following the administering as encompassed broadly by the instant claims. In the Amendment dated 05/26/26, Applicant stated clearly “The present application establishes that the timing of DR-18 administration is mechanistically critically to achieving the claimed ratio outcome. The specification describes at page 23 that mice were treated beginning at day 7 post-transplant – a specific temporal window chosen precisely because it precedes the accumulation of malignant cells in the bone marrow. The specification explains that this timing is mechanistically significant because TOX+TEFF cells lack self-renewal capacity, meaning that the ratio of these cells to malignant cells is time-dependent and critically sensitive to when administration begins relative to tumor burden” (Amendment at page 6, second full paragraph); and “The finding that DR-18 efficacy depends on the ratio of TOX+TEFF_3 cluster cells to malignant cells in the bone marrow and that this ratio is critically sensitive to administration timing relative to tumor burden was unexpected” (Amendment at page 8, fist sentence of second paragraph). Apart from the bone marrow transplant (containing hematopoietic stem cells), the instant specification also fails to provide sufficient guidance for an ordinary skill in the art on how use any other stem cell transplants to treat a malignancy in a subject as claimed broadly, particularly to attain the desired result of increasing the ratio of TOX+TEFF_3 cluster cells to malignant cells in the bone marrow of the subject. Additionally, in the Amendment dated 05/26/26, Applicant also stated “The specification of the present application establishes that the stem cell transplant context promotes a polyclonal myeloma-specific T-cell response that is largely mediated by CD8 T-cells, and that this polyclonal response is the biological substrate upon which DR-18 acts to expand TPEX and TOX+TEFF cells” (Amendment at page 5, last paragraph). Moreover, there is no evidence of record indicating or suggesting that any TOX+CD4+ TEFF cells and/or TOX+CD4+ TEFF_3 cluster cells are enriched or increased as a result of DR-18 treatment as encompassed broadly by the instant claims. Furthermore, there is also no evidence of record indicating or suggesting that any DR-18 treatment regimen other than the disclosed regimen of twice a week for 7-8 weeks of treatment would also result in the desired increased ratio of TOX+ TEFF_3 cluster cells to malignant cells in the bone marrow of the treated subject as encompassed broadly by the instant claims, particularly the physiological art is recognized as unpredictable (MPEP 2164.03). For example, would a single administration of DR-18 and/or administering DR-18 for 1 week, 2 week, or 3 weeks in the subject would also result in the desired results?
Since the prior art before the effective filing date of the present application failed to provide sufficient guidance regarding to the above issues, it is incumbent upon the present application to do so. Given the state of the prior art discussed above, coupled with the lack of sufficient guidance provided by the present application, it would have required undue experimentation for a skilled artisan to make and/or use as claimed broadly.
As set forth in In re Fisher, 166 USPQ 18 (CCPA 1970), compliance with 35 USC 112, first paragraph requires:
That scope of claims must bear a reasonable correlation to scope of enablement provided by specification to persons of ordinary skill in the art; in cases involving predictable factors, such as mechanical or electrical elements, a single embodiment provides broad enablement in the sense that, once imagined, other embodiments can be made without difficulty and their performance characteristics predicted by resort to known scientific laws; in cases involving unpredictable factors, such as most chemical reactions and physiological activity, scope of enablement varies inversely with degree of unpredictability of factors involved.
Moreover, the courts have also stated that reasonable correlation must exist between scope of exclusive right to patent application and scope of enablement set forth in the patent application (27 USPQ2d 1662 Ex parte Maizel.).
Accordingly, due to the lack of sufficient guidance provided by the specification regarding to the issues set forth above, the state and unpredictability of the relevant art, and the breadth of the instant claims, it would have required undue experimentation for one skilled in the art to make and use the instant broadly claimed invention.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Amended claims 1-3, 6-7 and 9-10 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. This is a new ground of rejection necessitated by Applicant’s amendment.
Claim 1 recites the limitation "the stem cell transplant" in the last line of the claim. There is insufficient antecedent basis for this limitation in the claim. This is because prior to this limitation there is no recitation of any stem cell transplant. Additionally, the claim also recites the limitation “the bone marrow” on line 2 of the claim. There is insufficient antecedent basis for this limitation in the claim. This is because prior to this limitation there is no recitation of any bone marrow. Accordingly, it is unclear which particular the stem cell transplant and the bone marrow do the limitations refer to. Clarification is requested because the metes and bounds of the claim are not clearly determined.
Similarly, claim 6 recites the limitation "the composition" in the first line of the claim. There is insufficient antecedent basis for this limitation in the claim. This is because prior to this limitation and in independent claim 1 from which claim 6 is dependent upon there is no recitation of a composition. Accordingly, it is unclear which particular “the composition” does the limitation refer to. Once again, clarification is requested because the metes and bounds of the claim are not clearly determined.
Claim 7 recites the limitation "the composition" in the last two lines of the claim. There is insufficient antecedent basis for this limitation in the claim. This is because prior to this limitation and in independent claim 1 from which claim 7 is dependent upon there is no recitation of a composition. Accordingly, it is unclear which particular “the composition” does the limitation refer to. Once again, clarification is requested because the metes and bounds of the claim are not clearly determined.
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.
Amended 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. This is because dependent claim 2 recites the limitation “wherein the subject received a stem cell transplant before the administering”. However, independent claim 1 from which claim 2 is dependent upon already recites the limitation “the subject that received the stem cell transplant”. 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. This is a new ground of rejection necessitated by Applicant’s amendment.
Conclusions
No claim is 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 or earlier communications from the examiner should be directed to Quang Nguyen, Ph.D., at (571) 272-0776.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s SPE, James Douglas (Doug) Schultz, Ph.D., may be reached at (571) 272-0763.
To aid in correlating any papers for this application, all further correspondence regarding this application should be directed to Group Art Unit 1631; Central Fax No. (571) 273-8300.
Any inquiry of a general nature or relating to the status of this application or proceeding should be directed to (571) 272-0547.
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/QUANG NGUYEN/
Primary Examiner, Art Unit 1631
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