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
This action is in response to the papers filed December 12, 2025.
Amendments
Applicant's amendments, filed December 12, 2025, is acknowledged. Applicant has cancelled Claims 1-37 and 43-55, amended Claims 38, 40-42, and 56-57, and withdrawn Claims 56-57.
Claims 38-42 and 56-57 are pending.
Election/Restrictions
Applicant has elected without traverse the invention of Group II, Claims 38-42, drawn to a method for treating a senescence-associated or an immune-inflammatory associated disease in a subject in need thereof, the method comprising the step(s) of:
a) obtaining information of a disease etiology of the subject;
wherein the disease etiology comprises a senescence-associated or an immune-inflammatory associated disease; and
(b)(i) administering to the subject cytotoxic CD4 T-cells (CD4-CTLs) and/or an agent capable of inducing CD4-CTLs differentiation and/or proliferation, thereby treating the senescence-associated disease; or
(b)(ii) administering an agent capable of inducing aTreg depletion and/or inhibition.
Within Group II, Applicant has elected without traverse the following species, wherein:
i) the alternative pharmaceutical composition is CD4 cytotoxic T-cells (CD4-CTLs);
iii) the alternative additional method step is isolating effector memory CD4 T-cells (EMs) from the subject and differentiating them into CD4-CTLs, as recited in Claim 40;
iv) the alternative biomarker is IL-6 during EM cultivations, and CD44 used for sorting the EMs, as recited in Claim 40; and
v) the alternative senescence-associated disease, immune-inflammatory associated disease, or autoinflammatory or autoimmune disease, is fibrosis, as recited in Claim 57.
Claims 38-42 and 56-57 are pending.
Claims 41-42 and 56-57 are pending but withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention, there being no allowable generic or linking claim.
Claims 38-40 are under consideration.
Priority
This application is a 371 of PCT/IL2021/051047 filed on August 25, 2021. Applicant’s claim for the benefit of a prior-filed application provisional application 63/073,183 filed on September 1, 2020, under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
Information Disclosure Statement
Applicant has filed Information Disclosure Statements on April 26, 2023, November 9, 2023, and May 7, 2025 that have been considered.
The information disclosure statements filed April 26, 2023, November 9, 2023, and May 7, 2025 fail to comply with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609 because 37 CFR 1.98(b) requires that each item of information in an IDS be identified properly. Each publication must be identified by publisher, author (if any), title, relevant pages of the publication, and date and place of publication. The date of publication supplied must include at least the month and year of publication, except that the year of publication (without the month) will be accepted if the applicant points out in the information disclosure statement that the year of publication is sufficiently earlier than the effective U.S. filing date and any foreign priority date so that the particular month of publication is not in issue.
See also MPEP 707.05(e) for electronic documents, including, but not limited to:
(D) reference to the unique Digital Object Identifier (DOI) number, or other unique identification number, if known.
Bibliographic information provided must be at least enough to identify the publication. author, title and date. For books, minimal information includes the author, title, and date. For periodicals, at least the title of the periodical, the volume number, date, and pages should be given.
NPL citations have been lined through for being defective of one or more requirements.
The signed and initialed PTO Forms 1449 are mailed with this action.
Specification
1. The prior objection to the disclosure is withdrawn in light of Applicant’s amendment to the specification to properly identify the trade name(s) and/or trade mark(s).
2. The disclosure is objected to because of the following informalities:
The use of the terms “BioLegend” and “Beckman Coulter”, used throughout the specification, are trade names or a marks used in commerce, has been noted in this application. The terms should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
See Office Action mailed March 27, 2025 in co-pending application 17/430,304.
Appropriate correction is required.
Claim Objections
3. Claim 38 stands objected to because of the following informalities:
Where a claim sets forth a plurality of elements or steps, each element or step of the claim should be separated by a line indentation, 37 CFR 1.75(i). See MPEP §608.01(m).
The second alternative administration step (lines 8-9) should be separated from the first alternative administration step (lines 6-8) by line indentation.
Appropriate correction is required.
4. Claim 40 is objected to because of the following informalities:
Each claim begins with a capital letter and ends with a period. See Fressola v. Manbeck, 36 USPQ2d 1211 (D.D.C. 1995)
The term “Wherein” (line 4) should not be capitalized.
Appropriate correction is required. See, for example, Claim 40, line 1, “wherein”.
5. Claim 40 is objected to because of the following informalities:
As a first matter, the claim recites two steps:
i) isolating…; and
ii) causing… differentiation… (lines 2-3).
Where a claim sets forth a plurality of elements or steps, each element or step of the claim should be separated by a line indentation, 37 CFR 1.75(i). See MPEP §608.01(m).
Appropriate correction is required. See Claim 38, steps a) and b), for example.
As a second matter, the ‘wherein… isolating EMs' limitation(s) (lines 7-8) should immediately follow the i) isolating step.
The ‘wherein… causing’ limitation(s) (lines 5-6) should immediately follow the ii) causing step.
Appropriate correction is required. See Claim 38, steps a) and b), respectively, for example.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
6. Claims 38-40 rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception without significantly more.
Claim 38 recites the step of obtaining information of a disease etiology of the subject.
With respect to Step 1, the claim is directed to a process, which is a statutory category of invention (Step 1: YES).
With respect to Step 2A, prong one, the judicial exception, the claim is directed to “obtaining information of a disease etiology of the subject”, whereby the step of obtaining information is an abstract idea or mental thought performed by the artisan, and thus directed to a judicial exception (Step 2A, prong one: YES).
With respect to Step 2A, prong two, the claim does not recite additional elements that integrate the judicial exception into a practical application. Rather, the step of obtaining information of a disease etiology of the subject is recited at a high level of generality and is considered merely extra-solution activity within the medical diagnostic field of use. The step of obtaining information of a disease etiology of the subject is recited at a high level of generality, is mere field of use, e.g. clinical medicine patient history, and does not impose a meaningful limit on the claim scope, nor the step of administering to said subject a pharmaceutical composition comprising cytotoxic CD4 T-cells. Thus, the claim does not integrate the mental analysis step into a practical application (Step 2A, prong two: NO).
With respect to Step 2B, the step of obtaining information of a disease etiology of the subject is recited at a high level of generality, is mere field of use, e.g. clinical medicine patient history, and does not impose a meaningful limit on the claim scope, nor the step of administering to said subject a pharmaceutical composition comprising cytotoxic CD4 T-cells. The claim does not recite additional elements that amount to significantly more than the judicial exception itself (Step 2B: NO).
Dependent claims are included in the basis of the rejection because they do not correct the deficiencies of the independent claim(s).
Claim Rejections - 35 USC § 112
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.
7. Claim 40 is 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.
While it is clear that the effector memory (EM) CD4+ T-cells are to be isolated and sorted using CD44 as a biomarker, the claim is considered indefinite as being incomplete for omitting essential steps, such omission amounting to a gap between the steps. See MPEP § 2172.01. The claim fails to recite the CD44 expression status of the effector memory (EM) CD4+ T-cells that are to be isolated and sorted per the claimed step(s), to wit:
i) CD4+, CD44+ effector memory T-cells; or, alternatively,
ii) CD4+, CD44- effector memory T-cells.
Appropriate correction is required.
Claim Rejections - 35 USC § 102
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 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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
8. Claim(s) 38-39 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Comoli et al (Infusion of autologous Epstein-Barr virus (EBV)–specific cytotoxic T cells for prevention of EBV-related lymphoproliferative disorder in solid organ transplant recipients with evidence of active virus replication, Blood 99: 2592-2598, 2002).
Instant specification discloses “senescence-associated disease” encompasses chronic infection (e.g. pg 3, lines 1-3).
With respect to Claim 38, Comoli et al is considered relevant prior art for having taught a method for treating a senescence-associated or an immune-inflammatory associated disease, to wit, chronic infection with EBV (e.g. Title), in a subject in need thereof, the method comprising the step(s) of:
a) obtaining information of a disease etiology of the subject (e.g. Abstract, “patients…at risk of developing EBV-associated post-transplantation lymphoproliferative disorders”); and
b) administering to the subject cytotoxic CD4 T-cells (e.g. Title; pg 2594, col. 2, Methods, CTL immunophenotypes, “a CTL line that was more than 70% CD4+”), thereby treating the senescence-associated disease (e.g. Abstract, “able to augment virus-specific immune response, reduce viral load in the recipients”).
With respect to Claim 39, Comoli et al taught wherein the cytotoxic CD4 T-cells are autologous to the subject (e.g. Title).
Thus, Comoli et al anticipate the claims.
9. Claim(s) 38-39 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Hunder et al (Treatment of Metastatic Melanoma with Autologous CD4+ T Cells against NY-ESO-1, N. Engl. J. Med. 358(25): 2698-2703, 2008).
Instant specification discloses “senescence-associated disease” encompasses cancer (e.g. pg 3, lines 1-3).
With respect to Claim 38, Hunder et al is considered relevant prior art for having taught a method for treating a senescence-associated or an immune-inflammatory associated disease, to wit, metastatic melanoma (e.g. Title), in a subject in need thereof, the method comprising the step(s) of:
a) obtaining information of a disease etiology of the subject (e.g. Summary, “patient with refractory metastatic melanoma”); and
b) administering to the subject cytotoxic CD4 T-cells (e.g. pg 2699, Methods, antigen-specific CD4+ T-cell clones”; pg 2700, col. 2, “the entire tumor regressed after infusion of the [antigen]-specific CD4+ T-cells”), thereby treating the senescence-associated disease (e.g. Summary, “We show that the transferred CD4+ T cells mediated a durable clinical remission”).
With respect to Claim 39, Hunder et al taught wherein the cytotoxic CD4 T-cells are autologous to the subject (e.g. Title).
Thus, Hunder et al anticipate the claims.
10. Claim(s) 38-39 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Bollard et al (Sustained Complete Responses in Patients With Lymphoma Receiving Autologous Cytotoxic T Lymphocytes Targeting Epstein-Barr Virus Latent Membrane Proteins, J. Clin. Oncol. 32: 798-808, 2013).
Instant specification discloses “senescence-associated disease” encompasses cancer (e.g. pg 3, lines 1-3).
With respect to Claim 38, Bollard et al is considered relevant prior art for having taught a method for treating a senescence-associated or an immune-inflammatory associated disease, to wit, Lymphoma (e.g. Title), in a subject in need thereof, the method comprising the step(s) of:
a) obtaining information of a disease etiology of the subject (e.g. Abstract, “high-risk or multiple-relapse patients”, “relapsed or resistant disease”); and
b) administering to the subject cytotoxic CD4 T-cells (e.g. pg 799, col. 1, Methods, “patient derived CTLs contained…. CD4+”; Figure 1a, legend, “[antigen]-specific CTLs…. CD4+”; pg 802, col. 1, “CTLs comprised… CD4+ T cells”), thereby treating the senescence-associated disease (e.g. pg 803, col. 1, “these CD4+ CTLs were cytotoxic and had antitumor activity in vivo”).
With respect to Claim 39, Bollard et al taught wherein the cytotoxic CD4 T-cells are autologous to the subject (e.g. Title).
Thus, Bollard et al anticipate the claims.
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 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 of this title, 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.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) 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.
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.
11. Claim(s) 40 is rejected under AIA 35 U.S.C. 103 as being unpatentable over Bollard et al (2013; of record), as applied to Claims 38-39 above, and in further view of Flaherty et al (Mouse Naïve CD4+ T Cell Isolation and In vitro Differentiation into T Cell Subsets, J. Visualized Experiments 98: e52739, 8 pages, doi:10.3791/52739; April 2015), Nish et al (T cell-intrinsic role of IL-6 signaling in primary and memory responses, eLife 3: e01949, 21 pages, doi:10.7554/eLife.01949, 2014), and Longhi et al (Interleukin-6 Is Crucial for Recall of Influenza-Specific Memory CD4+ T Cells, PLoS Pathogens 4(2): 8 pages, doi.org/10.1371/journal.ppat.1000006, 2008).
Determining the scope and contents of the prior art, and Ascertaining the differences between the prior art and the claims at issue.
With respect to Claim 38, Bollard et al is considered relevant prior art for having taught a method for treating a senescence-associated or an immune-inflammatory associated disease, to wit, Lymphoma (e.g. Title), in a subject in need thereof, the method comprising the step(s) of:
a) obtaining information of a disease etiology of the subject (e.g. Abstract, “high-risk or multiple-relapse patients”, “relapsed or resistant disease”); and
b) administering to the subject cytotoxic CD4 T-cells (e.g. pg 799, col. 1, Methods, “patient derived CTLs contained…. CD4+”; Figure 1a, legend, “[antigen]-specific CTLs…. CD4+”; pg 802, col. 1, “CTLs comprised… CD4+ T cells”), thereby treating the senescence-associated disease (e.g. pg 803, col. 1, “these CD4+ CTLs were cytotoxic and had antitumor activity in vivo”).
With respect to Claim 39, Bollard et al taught wherein the cytotoxic CD4 T-cells are autologous to the subject (e.g. Title).
Bollard et al taught that the patient’s isolated autologous CD4+ CTLs inherently and naturally comprises both effector memory and central memory CD4+ T cells (e.g. pg 799, col. 1, Methods).
Bollard et al do not teach wherein the method further comprises the step(s) of:
i) isolating CD4+ T effector memory cells from a subject using CD44 as a marker, and
ii) culturing said CD4+ T effector memory cells in the presence of IL-6, thereby inducing differentiation of said CD4+ T effector memory cells
However, prior to the effective filing date of the instantly claimed invention, and with respect to Claim(s) 40, Flaherty et al is considered relevant prior art for having taught a method of isolating primary memory T cells from a subject, the method comprising the step of using CD44 as biomarker (e.g. pg 3, Step 4, sorting naïve CD4+ T cells, “label…with….antibodies directed against…CD44”), thereby sorting and isolating effector/memory CD4+ cells (CD44+) (e.g. Figure 2, legend, “gate… then sort CD44- from effector/memory CD44+ CD4+ cells).
Nish et al is considered relevant prior art for having taught that IL-6 enables T cell activation by making them less sensitive to the suppressive activity of Tregs, protects CD4+ T cells from anti-CD3-induced apoptosis and Fas-mediated cell death, and plays a role in the generation of functional memory CD4+ T cells, being essential for memory CD4+ T cell function (e.g. pg 3, paras 1 and 3; pg 11, last para).
Longhi et al is considered relevant prior art for having taught that CD4+ memory T cells are critically dependent upon IL-6, and the effect of IL-6 includes its ability to suppress CD4+ Tregs, thereby facilitating the activity of virus-specific memory CD4+ T cells and favoring pathogen clearance of the cytopathic viruses (e.g. Abstract).
Resolving the level of ordinary skill in the pertinent art.
People of the ordinary skill in the art will be highly educated individuals such as medical doctors, scientists, or engineers possessing advanced degrees, including M.D.'s and Ph.D.'s. Thus, these people most likely will be knowledgeable and well-read in the relevant literature and have the practical experience in molecular biology, cell biology, and immunology. Therefore, the level of ordinary skill in this art is high.
"A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton." KSR International Co. v. Teleflex Inc., 550 U.S. ___, ___, 82 USPQ2d 1385, 1397 (2007). "[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle." Id. Office personnel may also take into account "the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at ___, 82 USPQ2d at 1396.
Considering objective evidence present in the application indicating obviousness or nonobviousness.
The focus when making a determination of obviousness should be on what a person of ordinary skill in the pertinent art would have known at the time of the invention, and on what such a person would have reasonably expected to have been able to do in view of that knowledge. This is so regardless of whether the source of that knowledge and ability was documentary prior art, general knowledge in the art, or common sense. M.P.E.P. §2141.
The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). See also In re Kotzab, 217 F.3d 1365, 1370, 55 USPQ2d 1313, 1317 (Fed. Cir. 2000) (setting forth test for implicit teachings); In re Eli Lilly & Co., 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (discussion of reliance on legal precedent); In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings); and Ex parte Levengood, 28 USPQ2d 1300 (Bd. Pat. App. & Inter. 1993) (reliance on logic and sound scientific reasoning). See MPEP §2144.
Prior to the effective filing date of the instantly claimed invention, it would have been obvious to one of ordinary skill in the art to modify the method of Bollard et al to further comprise the steps of isolating CD4+ effector memory T cells from the patient using CD44 as a marker, and culturing said cells with IL-6, in a method of treating a senescence-associated disease with a reasonable expectation of success because those of ordinary skill in the art previously recognized the scientific and technical concepts that:
i) using CD44 as a biomarker had been successfully reduced to practice to isolate primary memory T cells from a subject (Flaherty et al); and
ii) IL-6 enables T cell activation by making them less sensitive to the suppressive activity of Tregs, protects CD4+ T cells from anti-CD3-induced apoptosis and Fas-mediated cell death, plays a role in the generation of functional memory CD4+ T cells, being essential for memory CD4+ T cell function (Nish et al), that CD4+ memory T cells are critically dependent upon IL-6, thereby facilitating the activity of antigen-specific memory CD4+ T cells, including favoring pathogen clearance of the cytopathic viruses (Longhi et al).
It is proper to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741,82 USPQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
The cited prior art meets the criteria set forth in both Graham and KSR, and the teachings of the cited prior art provide the requisite teachings and motivations with a clear, reasonable expectation of success. Thus, the invention as a whole is prima facie obvious.
Conclusion
12. No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KEVIN K. HILL whose telephone number is (571)272-8036. The examiner can normally be reached 12pm-8pm EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Tracy Vivlemore can be reached at 571-272-2914. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
KEVIN K. HILL
Examiner
Art Unit 1638
/KEVIN K HILL/Primary Examiner, Art Unit 1638