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 1-6, 8-9, 12-13, and 17 are cancelled.
Claims 7, 10-11, and 14-16 are pending and under examination on the merits.
Priority
This application is a CON of 15/738,498 12/20/2017 PAT 11,567,065 which is a 371 of PCT/US2016/039313 06/24/2016 which claims benefit of 62/183,997 06/24/2015.
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e)or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has notcomplied with one or more conditions for receiving the benefit of an earlier filing dateunder 35 U.S.C. 119(e) as follows:
The later-filed application must be an application for a patent for an inventionwhich is also disclosed in the prior application (the parent or original nonprovisionalapplication or provisional application). The disclosure of the invention in the parentapplication and in the later-filed application must be sufficient to comply with therequirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112,except for the best mode requirement. See Transco Products, Inc. v. PerformanceContracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
Claims 7, 10-11, and 14 are present in the original disclosure of theprovisional application and have the priority date of 06/24/2015 (finding support in US Provisional Application No. 62/183,997).
Claims 15-16 have the priority date of 06/24/2016 (finding support in US Patent Application No 15/738,498, but not in US Provisional Application No. 62/183,997 which, while mentioning the method in the context of CMV and depicting differences over 1 standard deviation as significant, does not even mention administration of a composition suitable for treating a suspected virulent).
Withdrawn Objections/Rejections
The objection to the specification is withdrawn as corrected by the 06/17/2026 amendments. The sequence compliance objection is withdrawn as corrected by the 06/17/2026 amendments. The objections to claims 7, 14, and 16 presented in the previous office action are withdrawn as corrected by the 06/17/2026 claim amendments. The rejections of the claims for lack of written description are withdrawn in light of the 06/17/2026 claim amendments. The rejections of the claims for lack of enablement for a method where the T cells are not labeled with a Ca2+ fluorophores are withdrawn in light of the narrowing 06/17/2026 claim amendments. The rejections of claims 7, 10-11, and 15 under 35 USC §112(b) are withdrawn in light of the 06/17/2026 claim amendments. The rejections of claims 7 and 10-11 under 35 USC §103 and for double patenting are withdrawn and replace with the rejections as presented in this Office Action to better account for the newly amended claim scope resulting from the 06/17/2026 claim amendments.
Maintained-Claim Interpretation
A preamble is generally not accorded any patentable weight where it merely recites the
purpose of a process or the intended use of a structure, and where the body of the claim does not depend on the preamble for completeness but, instead, the process steps or structural limitations are able to stand alone. See In re Hirao, 535 F.2d 67, 190 USPQ 15 (CCPA 1976) and Kropa v. Robie, 187 F.2d 150, 152, 88 USPQ 478, 481 (CCPA 1951).
The preamble of claim 7 does not breathe life and meaning into the claim and is therefore not deemed to lend patentable weight to the method. The claim body, comprising the active steps and reagents required for the claimed method are what is being examined for a determination of patentability.
The claims are being interpreted as requiring steps and elements allowing for measurement of intracellular calcium signaling.
Recitations of terms such as peptide-MHC oligomers, peptide-MHC, etc (noting that many terms are synonymously, though inconsistently used throughout the instant disclosure) are interpreted to encompass an antigen that binds MHC type I of the T cell (see for example, paragraphs 0011, 0014, 0016-0017, 0021).
Maintained-Claim Rejections - 35 USC § 112
35 USC § 112(a)
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.
Enablement
Claims 14-16 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
MPEP 2164.01(a) states that in order to determine compliance with the enablement requirement, the Federal Circuit developed a framework of factors in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), referred to as the Wands factors to assess whether any necessary experimentation required by the specification is “reasonable” or is “undue.”
These factors include but are not limited to: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
The breadth of the claims
Claims 14-16 are broadly directed to a method to determine the frequency and functional activity of antigen-specific CD8 T cells through an assay which measures calcium-dependent fluorescence intensity which informs a downstream calculated fraction of responding T cells with the specify of interest. The specification discloses a method in which the rate of calcium signaling as measured by the claimed assay is used to inform downstream determinations of T cell frequency and functional activity which are used to form conclusions regarding immunocompetency and treatment.
The nature of the invention
Claims 14-16 are broadly directed to a method to determine the frequency and functional activity of antigen-specific CD8 T cells through an assay which measures calcium-dependent fluorescence intensity which informs a downstream calculated fraction of responding T cells with the specificity of interest. The claims are directed to biological subject matter which is understood to be complex and often unpredictable.
The state of the prior art
The state of the prior art supports that different assay methods in CD8 T cells often result in different measured binding kinetics, even when the same pMHC and TCR are used and that weaker antigens have different kinetics than stronger antigens (see for Edwards et al (Immunol Res. 2011 May;50(1):39-48. doi: 10.1007/s12026-011-8204-3) at for example, paragraph 3 of page 4)). Moreover, Carnahan et al (Pharmacotherapy. 2024;44:698–700; DOI: 10.1002/phar.4605) teach that underpowered studies that report significant findings are at an elevated risk of incorrectly identifying the sign and/or magnitude of a real effect. In a well-designed clinical trial meant to test the effect of an intervention, the target sample size is determined by specifying a minimum clinically important intervention effect that the investigators want to be able to detect and estimating the variability in or frequency of the outcome. This is usually based on prior knowledge or data. A decision is then made about what the achievable level of power to detect a particular magnitude of effect is, with conventions to ensure power of at least 80%–90%, leaving a 10%–20% chance that a true effect of that size will be missed. Small pilot studies are often underpowered. The effect estimates from these studies can have wide confidence or credible intervals, reflecting substantial uncertainty about true intervention effects, and variability in the outcome measures may be poorly estimated by small samples. Effects observed in these studies may be entirely due to chance, and effect estimates in the opposite direction of the true effect are more likely in small studies. Even statistically significant findings from small studies are more likely to be false positive findings due to random chance than those from larger studies when the same alpha is used. To make matters worse, if a study is underpowered to detect clinically meaningful effects, its use as a screening tool would be likely to exclude meaningful interventions from future study if effect size is not considered (see for example, pages 698-699).
The level of one of ordinary skill
As the claims are directed to determination of antigen-specific CD8 T cell frequency and functional activity, the artisan is presumed to be highly skilled, tending to have an advanced degree (such as a Ph.D. or an M.D.).
The level of predictability in the art
The art supports that different measures will result in different observed binding kinetics (which results in different Ca2+ fluorescence which indirectly represents measured frequency and functional activity of antigen-specific CD8 T cells. The art further supports that the strength of the pMHC plays a role in determining observed kinetics and supports that underpowered data are unpredictable for supporting a generalized conclusion, noting that the effect noted may be a false positive or an idiosyncratic response (see supra).
(F) The amount of direction provided by the inventor
Applicant does not disclose the claimed method that does not involve determination of a relative rate of calcium signaling fluctuation in response to pMHC. Applicant only discloses 1 example of the method (presumed to use the noted CMV epitopes from ThinkPeptide; see paragraph 00104 of the instant specification) where the rate of calcium fluctuation/signaling of healthy/control T cells is compared to the rate of calcium fluctuation/signaling of T cells taken from a bone marrow transplant patient on the 152nd day after the transplant (both sets of T cells being CMV specific). The instant disclosure only clearly disclose rate of response (MFI/time) data, said data showing unpredictable response rate among strong, weak, and very weak antigens (see for example, figure 4A and paragraphs 00111 and 00113 at pages 25-26 of the specification).
The existence of working examples
Applicant discloses 1 working example (see supra and instant figure 7) (noting that figures 2-6 do not clearly disclose any particular antigen and are not therefore working examples to guide the artisan).
The quantity of experimentation needed to make or use the invention based on the content of the disclosure
The case is directed to biological subject matter, which is by nature complex. There is only one working example provided (which is notably not commensurate with the breadth of what is claimed) and the state of the art fails to step in to provide enablement where the instant disclosure is lacking. Note that the data serving as proof of concept is woefully underpowered calling into question whether the effect observed is supported or indicates what Applicant believes may be true, but has not yet enabled. The artisan would be forced into burdensome experimentation so as to effectively invent what applicant only suggests may be possible.
Thus, in light of the contradictory findings in the prior art, the method is not deemed to be supported because even if the claims were to be amended to require determination of a relative Ca2+ signaling fluctuation rate, the data upon which the Application relies for proof of concept is so underpowered that a determination of enablement is precluded where the prior art fails to provide enablement for the method indicating a particular immune state, and treatment to be administered in the setting of CMV, or even the cutoff of +/->1 standard deviation of a control rate of Ca2+ fluorescence.
Newly Necessitated-Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim(s) 7 is/are rejected under 35 U.S.C. 103 as being unpatentable over Su et al (J Immunol 1993; 151:658-667; citation 13 under the Non-Patent Literature heading of the 06/10/2024 IDS) in view of Steenblock et al (Mol Ther. 2008 Apr;16(4):765-72. doi: 10.1038/mt.2008.11. Epub 2008 Mar 4), Li et al (J Biol Chem. 2009 Jul 31;284(31):21001-10. doi: 10.1074/jbc.M109.002865. Epub 2009 May 29), ATCC (TS2/4.1.1; HB-244; obtained from: file:///C:/Users/agao/OneDrive%20-%20US%20Patent%20and%20Trademark%20Office/Documents/2ered/18065736/TS2_4.1.1%20-%20HB-244%20_%20ATCC.pdf (accessed 08/13/2026)), Shin et al (Cytokine. 2013 February ; 61(2): 485–490. doi:10.1016/j.cyto.2012.11.024), ThermoFisher (Isolation of Untouched Human T cells from Peripheral blood Mononuclear Cells (PBMC), ThermoFisher Scientific, obtained from: https://www.thermofisher.com/us/en/home/references/protocols/proteins-expression-isolation-and-analysis/cell-separation-methods/human-cell-separation-protocols/isolation-of-untouched-human-t-cells-.html#pro1 (available as of May 2008)(see google screen capture as further the screen capture from Google search further evidencing the date of availability (obtained from: https://www.google.com/search?q=protocol+for+isolation+of+T+cell+from+patient+pbmc+sample+for+personalized+medicine&safe=active&sca_esv=db2351f46a6aa745&source=lnt&tbs=cdr%3A1%2Ccd_min%3A%2Ccd_max%3A2008&tbm=; accessed 02/26/2026), and Gering et al ( J Colloid Interface Sci. 2002 Aug 1;252(1):50-6. doi: 10.1006/jcis.2002.8415), as evidenced by Kapustay et al (US 6919077 B2).
Regarding claim 7, a preamble is generally not accorded any patentable weight where it merely recites the purpose of a process or the intended use of a structure, and where the body of the claim does not depend on the preamble for completeness but, instead, the process
steps or structural limitations are able to stand alone. See In re Hirao, 535 F.2d 67, 190
USPQ 15 (CCPA 1976) and Kropa v. Robie, 187 F.2d 150, 152, 88 USPQ 478, 481
(CCPA 1951).
In this case, the body of the claim does not depend on the preamble for completeness
and the preamble is not given patentable weight.
Su et al teach a method comprising using an increase of cellular calcium ion as a measure of T-cell activation wherein peptide-dependent activation, recognized by MHC I (implicitly taught to be expressed by CD8+ T cells), of CD8+ T cell lymphocyte depends upon cell to cell contact (see for example, the abstract and paragraph 1 of column 1 of page pages 658 and Fig. 8 at and 664, respectively). Su et al teach that TCR molecules on a CD8+ T cell do not interact with peptide-MHC-I complexes on the same cell and only cells CD8+ that are in contact to one another display an increase in Ca level in the presence of the cognate peptide (see for example, paragraph 1 of column 1 at page 659). This suggests that the immobilized T cells were a monolayer upon the surface.
In particular Su et al teach labeling T cells with Ca2+ sensitive fluorophore (see for example, paragraph 3 of column 1 at page 660) and adhering cells on a glass coverslip (which is held to make obvious immobilization on a glass well bottom as the chemical/mechanical process of the required adherence/immobilization is the same and would function predictably on any substantially flat surface comprised of glass) and measuring the level of fluorescence in all individual T cells to collect baseline measurements of Ca2+ with laser cytometry (see for example, paragraph 2 at column 2 at page 660). Su et al teach adding a single or multiple peptide epitopes such as for example Ov-8 peptide, that is recognized in association with MHC I by anti-OVA (antigen-specific) CD8 T cells, and measuring the level of fluorescence in every individual T cell by taking a second image of the T-cell monolayer on the glass coverslip (see for example, page 660 at paragraph 2 at column 2). An increase in calcium is seen in 4G3 CD8+ T cells which are in contract with each other, as for example by gentle centrifugation (see for example, Figs 8-9 at pages 664-665), as compared to baseline (shown in for example, Fig 8 at page 664) which reads on identifying an increase in intracellular Ca2+ level and fluorescence intensity for every individual T cell after subtracting fluorescence intensity for every individual T cell measured before the addition of the stimulatory pMHC from which a fraction of responding and non-responding cells (presumably responding/antigen-specific cells show an increase in Ca2+ and non-responding/antigen-non-specific cells will not show an appreciable increase in Ca2+ relative to baseline) may be identified/quantified/analyzed for functional activity. Su et al further teach measuring changes in number of individual T cells with increased intracellular fluorescence as a function of time to provide the kinetic curve of the TCR-mediated Ca2+ signaling (see for example, figure 664 at Fig. 8 from which it can be seen that all individual T cells that were closely packed by gentle centrifugation show increase fluorescence as a function of time as compared to baseline (i.e. cells that were not incubated with the peptide); this is deemed to make obvious subtracting the fluorescence intensity for every T cell measured before the addition of the peptide-MHC oligomers from intracellular Ca2+ level and fluorescence intensity after the addition of the peptide-MHC oligomers).
Su et al do not teach that the T cells are immobilized on a glass bottom of a well using a capture peptide or capture antibody.
However, Steenblock et al teach that efficient T-cell stimulation and proliferation in response to specific antigens is a goal of immunotherapy against infectious disease and cancer (see for example, sentence 1 of paragraph 1 of column 1 at page 765). Steenblock et al further teach an assay where aAPC–T-cell binding was visualized by immobilizing B3Z cells (a T-cell line) to poly-L-lysine-coated cover slips, which were washed three times and blocked, and then incubated with a 5 mg/ml solution of targeted microparticle aAPCs containing encapsulated Rhodamine B and surface bound anti-CD3 and anti-CD28 for 1 hour at 4 °C (see for example, Fig 2 and its caption at page 766 and the fluorescence microscopy section of column 2 of page 771) . Here, Poly-L-lysine would represent the claimed capture protein.
Su et al and Steenblock et al do not explicitly teach that the T cells are further/additionally immobilized using a TS2/4 monoclonal antibody (admittedly made from the TS2/4 hybridoma purchased from ATCC; see paragraph 0065 at page 16 of the instant specification).
However, Li et al teach leukocyte function-associated antigen-1 (LFA-1) plays an important role in regulating leukocyte adhesion and T cell activation. LFA-1 participates in the formation of the immunological synapse, which regulates T cell activation synergistically with TCR engagement. The immunological synapse is a specialized structure that forms between the T cell and the APC or target cell. The function of the immunological synapse is to facilitate T cell activation and signal transduction (see for example, page 21001).
Su et al, Steenblock et al, and Li et al do not explicitly teach the TS2/4 monoclonal antibody.
However, ATCC teaches that the TS2/4 monoclonal antibody (mAb) binds but does not inhibit LFA-1 activity (see page 3, for example; note that Kapustay et al evidence that the TS2/4 antibody from ATCC was known in the art and publicly available at least as of 2005, see for example column 5).
Su et al, Steenblock et al, Li et al, and ATCC do not explicitly teach how to attach an antibody to a glass surface such as a well plate.
However, Gering et al teach means for attaching a generic antibody to glass surfaces via the oxidized sugar moiety, which proved to be an adequate method for providing uniform coverage of active antibody (see for example, the abstract at page 50 and column 1 of page 56)
Su et al, Steenblock et al, Li et al ATCC, and Gering et al, do not explicitly teach using a CMV peptide (reading on the peptide-MHC oligomer as instantly recited as the only example and CMV-specific example described in the disclosure uses the ProMix CMV peptide mix as disclosed at paragraph 00104 at page 23 of the instant specification).
However, Shin et al, investigating age-related differences in CD8+ T cell activity and maintenance in young versus elderly healthy subjects upon stimulation with CMV-antigen(s) (using age-matched controls), teach that commercially available human CMV antigens in a pp65 pool purchased from ProMix were contacted with CMV-specific CD8+ T cells from PBMCs from CMV+ individuals to study CD8+ T cell activation, proliferation, and cytokine production (see for example, the abstract at page 1 and section 2.2 at page 3).It is noted that Applicant used commercially available T cells from PBMC indicating that such isolation and use in commonly known in the art (see for example, paragraph 00102 of the instant specification). Therefore, this limitation is considered to be admitted prior art by Applicant. However, even if Applicant were to argue the admission of said prior art, this limitation would still be deemed obvious because ThermoFisher teaches a protocol for isolation of T cells from PBMC and sells kits and products therefore (see the reference in its entirety).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of the combined references. The artisan would have been motivated to make and use the invention as claimed because Su et al teach a method for determining T cell activation (by rate of intracellular Ca2+ flux) in response to a pMHC I antigen (to be chosen for the desired application) relative to baseline (include subtraction of pre-antigen exposure/background fluorescence from post-antigen exposure fluorescence) where Steenblock et al teach that efficient T-cell stimulation and proliferation in response to specific antigens is a goal of immunotherapy against infectious disease and cancer. The artisan would have found it obvious to substitute a glass well plate for a coverslip to enable analysis of multiple samples and or/conditions/concentrations of pMHC simultaneously where the chemistry and mechanics of immobilization among substantially flat glass surfaces and generically recited CD8 T cells would have been predictable altered in to use a glass well. Additionally, the artisan would have found it obvious to use antigen-specific T cells isolated from PBMC from a patient as an art-known, relatively non-invasive means for obtaining a patient-specific sample for personalized medicine. Where poly-L-lysine and anti-LFA-1 (TS2/4 mAb) antibody are both taught in the art to be ways of immobilizing an LFA-1+, CD8+ T cell to a glass surface, the combination of the poly-L-lysine and anti-LFA-1 would have been prima facie obvious because they are being used to accomplish the purpose for which they are taught to be individually effect in the art (see MPEP §2144.06; noting that the instant disclosure seems to imply that both Poly-l-lysine and a capture antibody are used for immobilization (see for example, figure1)). In light of the cited prior art teachings, where the artisan desired to examine the activation/activity of CD8+ T cells in response to CMV antigen stimulation, the artisan would have found it obvious to use an antibody which does not inhibit the activity of LFA-1 (such as TS2/4) and to stimulate the T cells with CMV antigens such as the ProMix peptide blend (understood to be a peptide-MHC oligomer as recited because this specific blend is the only example which Applicant describes as relevant to CMV through the disclosure). The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Claim(s) 10-11 is/are rejected under 35 U.S.C. 103 as being unpatentable over Su et al Steenblock et al, Li et al, Shin et al, ATCC, Gering et al, and ThermoFisher, as evidenced by Kapustay et al, as applied to claim 7 above, in further view of Maecker et al (Cytometry Part A Doi 10.1002/cyto.a, first published Aug. 2006, obtained from: https://onlinelibrary.wiley.com/doi/epdf/10.1002/cyto.a.20333).
Regarding claims 10-11, the combined references make obvious the method of claim 7, but do not explicitly teach comparison of a pathogen-specific or tumor-specific CD8 T cell to a control or a control that is a T cell sample from a healthy patient/donor.
However, Maecker et al teach that any experiment may, and probably should, contain at least three types of controls: setup (or instrument) controls, specificity (or gating) controls, and biological comparison controls, where biological comparison controls are those that provide biologically relevant comparison conditions, for example, unstimulated samples or healthy donor samples (see for example, column 1 of page 1037), noting that comparison of a disease phenotype and a healthy control is an art-known comparison and control in biological science (see for example, column 1 of page 1042).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of the combined references. The artisan would have found it obvious to use a control that is a corresponding sample (of PBMC isolated T cells) from a healthy donor to serve as a biological control relative to the test sample for comparative analysis of a disease state relative to a healthy/normal state (as taught by Maecker et al). The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Newly Necessitated-Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claim 7 is rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-3 of U.S. Patent No. 11567065 B2 (reference A). Although the claims at issue are not identical, they are not patentably distinct from each other because the reference claims and instant claims are directed to methods with substantially the same active steps and reagents.
Reference A claims a method for detection of the frequency of T cells responding to a single or multiple antigenic peptide epitope(s), by fluorescent microscopy comprising:
(a) coating a glass surface with an agent capable of binding an antibody, wherein the agent comprises poly-L-lysine,
(b) immobilizing on the glass surface of (a) an antibody that binds to a receptor on the T-cell surface without interfering with Ca2+ flux, wherein the antibody comprises the TS2/4 monoclonal antibody specific for Lymphocyte Function Associated Antigen 1 (LFA-1), to form a T-cell capturing surface,
(c) adding cloned or polyclonal T cells or gamma/delta T cells labeled with Ca2+ sensitive fluorophore to the T-cell capturing surface of (b) to generate a continuous monolayer of the T cells on the glass surface,
(d) taking a first image of the T-cell monolayer to determine a level of background fluorescence in every individual cell,
(e) performing antigen stimulation of the T-cell monolayer comprising adding a single or multiple antigenic peptide epitope(s) or live target cells presenting potential antigenic peptide epitope(s) to the T-cell monolayer wherein the antigenic peptide epitopes are capable of binding to MHC proteins expressed on the T-cell surface to form a peptide-MHC complex,
(f) measuring the level of fluorescence in every individual T cell of the stimulated T-cell monolayer of (e), by taking a second image of the T-cell monolayer of (e), wherein an increase of intracellular fluorescence of individual cells indicates T cells responding to the single or multiple antigenic peptide epitopes (understood to allow for identification of antigen-specific T cells); and
g) quantifying the frequency of responses of individual T cells to a single or multiple antigenic peptide epitopes by subtracting intracellular fluorescence of the first image measured prior to addition of said single or multiple antigenic peptide(s) epitopes from that acquired after the second image following addition of said single or multiple antigenic peptide epitope(s), wherein the number of individual T cells that exhibit fluorescence greater than background fluorescence are quantified to calculate the number of responding cells per the number of added cloned or polyclonal T cells , wherein the T cells may be CD8+ T cells from PBMC, wherein the method further comprises measuring the kinetics (rate) of Ca2+ flux in the T cell (intracellular and presumptively within each individual cell in light of the language employed in the drafting of the claim) that form the monolayer on the surface by repeating step (f) over time to determine a kinetic curve (see for example, claims 1-3 of reference A).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosure of reference A. The artisan would have been motivated to make and use the invention as claimed because As part of determining obviousness, it is to be considered that the combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results. When a work is available in one field of endeavor, design incentives and other market forces can prompt variations of it, either in the same field or a different one. If a person of ordinary skill can implement a predictable variation, § 103 may bar its patentability. When considering obviousness of a combination of known elements, the operative question is thus “whether the improvement is more than the predictable use of prior art elements according to their established functions,” (see MPEP 2141. I.)). Here, the active method steps are essentially the same where any deviations are small and predictable variations on the reference method. The reagents used are substantially the same. Where the same active steps and measurements are taken using substantially similar reagents, the method of reference A is deemed to make obvious the method of instant claim 7. The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Claims 10-11 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-3 of U.S. Patent No. 11567065 B2 (reference A), as applied to claim 7 above, in view of Maecker et al (Cytometry Part A Doi 10.1002/cyto.a, first published Aug. 2006, obtained from: https://onlinelibrary.wiley.com/doi/epdf/10.1002/cyto.a.20333). Although the claims at issue are not identical, they are not patentably distinct from each other because the reference claims and instant claims are directed to methods with substantially the same active steps and reagents
Regarding claims 10-11, reference A makes obvious the method of claim 7, but does not explicitly teach comparison of a pathogen-specific or tumor-specific CD8 T cell to a control or a control that is a T cell sample from a healthy patient/donor.
However, Maecker et al teach that any experiment may, and probably should, contain at least three types of controls: setup (or instrument) controls, specificity (or gating) controls, and biological comparison controls, where biological comparison controls are those that provide biologically relevant comparison conditions, for example, unstimulated samples or healthy donor samples (see for example, column 1 of page 1037), noting that comparison of a disease phenotype and a healthy control is an art-known comparison and control in biological science (see for example, column 1 of page 1042).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of the combined references. The artisan would have found it obvious to use a control that is a corresponding sample (of PBMC isolated T cells) from a healthy donor to serve as a biological control relative to the test sample for comparative analysis of a disease state relative to a healthy/normal state (as taught by Maecker et al). The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Claim 7 and 10-11 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 15-25 of U.S. Patent Application No. 19/058,712 (reference B).
This is a provisional nonstatutory double patenting rejection.
Reference B claims a method of evaluating a T cell response comprising: a) binding mammalian T cells labeled with a Ca2+ sensitive fluorophore to a glass surface using a capturing protein to form a monolayer; b) exposing the T cells obtained in a) with an antigen that is capable of binding to Major Histocompatibility Complex (MHC) proteins, wherein the MHC proteins bind to the T cells; c) measuring the intracellular fluorescence of the T cells obtained in step b) wherein an increase of intracellular fluorescence in individual cells indicates T cells have been activated by the antigen; d) characterizing the T cell response as one of a rapid sustained response, a delayed sustained response, an oscillating response, or a sporadic transient response e) comparing the T cell response to a control, wherein the T cells are bound to the surface via attachment to a capturing protein, wherein the capturing protein binds to a receptor on the surface of the T cell without interfering with Ca2+ flux and wherein the capturing protein comprises a TS2/4 monoclonal antibody specific for lymphocyte function-associated antigen 1. (see for example, claims 15-17 of reference B). Reference B further claims the method wherein measuring the intracellular fluorescence of T cells comprises herein measuring the intracellular fluorescence of T cells comprises: a) measuring an initial background fluorescence of the T cell labeled with a Ca2+ sensitive fluorophore prior to exposure to the antigen; b) measuring fluorescence of the T cell labeled with a Ca2+ sensitive fluorophore following exposure to the antigen; and c) subtracting the initial background fluorescence of the T cell labeled with a Ca2+ sensitive fluorophore from the fluorescence following exposure to the antigen (see for example, claim 18 of reference B), wherein the antigen is a pathogen-specific or tumor-specific antigen (see for example, claim 20 of reference B). Reference B further claims that said method may be applied to determining immune status which informs administration of a suitable treatment where this application of the method requires comparison of the measured T cell response to a control (see for example, claims 21-23 of reference B), wherein said control may be the responses or a predetermined quality thereof observed from the responses of T cells from healthy patients to antigen (see for example, claim 25 of reference B).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosure of reference A. The artisan would have been motivated to make and use the invention as claimed because As part of determining obviousness, it is to be considered that the combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results. When a work is available in one field of endeavor, design incentives and other market forces can prompt variations of it, either in the same field or a different one. If a person of ordinary skill can implement a predictable variation, § 103 may bar its patentability. When considering obviousness of a combination of known elements, the operative question is thus “whether the improvement is more than the predictable use of prior art elements according to their established functions,” (see MPEP 2141. I.)). Here, the active method steps are essentially the same where any deviations are small and predictable variations on the reference method. The reagents used are substantially the same. Where the same active steps and measurements are taken using substantially similar reagents, the method of reference B is deemed to make obvious the method of instant claims 7 and 10-11. The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Applicant’s Arguments and Reponses
A. Applicant requests withdrawal of the rejection of claims 14-16 for lack of enablement (see pages 15-17 of the 06/17/2026 remarks).
Response: Applicant argues that “…the invention need not contain an example if the invention is otherwise disclosed in such manner that one skilled in the art will be able to practice it without an undue amount of experimentation. In re Borkowski, 422 F.2d 904, 908 (C.C.P.A. 1970). The test of enablement is not whether any experimentation is necessary, but whether, if experimentation is necessary, it is undue. MPEP §2164.01 (citing In re Angstadt, 537 F.2d 498, 504 (C.C.P.A. 1976)),” (see for example, page 15 of the 06/17/2026 remarks). The problem is that ne skilled in the art would not be able to practice it without an undue amount of experimentation. Applicant’s own data show unpredictability of T cell response/ activation (as a measure of MFI/time) across antigens that are arbitrarily disclosed to be strong, weak, or very weak (see for example, figure 4A). The Examiner has cited art which teaches unpredictability of CD8+ T responses assays to different antigens [excerpted from above: “…different assay methods in CD8 T cells often result in different measured binding kinetics, even when the same pMHC and TCR are used and that weaker antigens have different kinetics than stronger antigens (see for Edwards et al (Immunol Res. 2011 May;50(1):39-48. doi: 10.1007/s12026-011-8204-3) at for example, paragraph 3 of page 4))”]. Where there is demonstrated unpredictability, either the prior art or the instant disclosure must step in to provide enablement. A search of the prior art fails to enable the scope of claims 14-16 as presently drafted. The instant specification only provides 1 very underpowered example, noting that while the Examiner makes a good faith interpretation that the ProMix CMV antigen blend is used as the peptide-oligomer, even this is not clearly disclosed (such as by a catalogue number, product link, or description of the antigens used in the blend). Therefore, even this this example, does not enable the scope of CMV-related antigens as the peptide-oligomers, let alone the wise scope of any peptide-oligomer. The artisan is asked to determined from the breadth of all possible peptide-oligomers, which members of the genus claimed would result in a MFI/time output (response/activation curve) whereby a decrease/reduction by more than one standard deviation indicates a compromised immune system. The Examiner has considered the disclosure at page 24 and table 3 of the specification and at figure 7 as requested by Applicant. The Examiner has further considered the disclosure at pages 24-27. These examples are not specific. The disclosure of the GL9 (Flu-derived) peptide does specifically identify a particular peptide-MHC oligomer/antigen for use in the assay. However, this antigen is only disclosed to function with CER43 T cells and even this disclosure does not provide enabling data for using a reduction in frequency or efficacy of responding T cells (MFI/time) by more than one standard deviation relative to a control frequency or efficacy of responding T cells (MFI/time) as a cutoff for indicating a compromised immune system. The disclosure using ThinkPeptide ProMix CMV peptide pool is further not disclosed to clearly indicate the antigens used, that the antigens would work with any CD8+T cell, or that a reduction in frequency or efficacy of responding T cells (MFI/time) by more than one standard deviation relative to a control frequency or efficacy of responding T cells (MFI/time) as a cutoff for indicating a compromised immune system. Where the Examiner has made a prima facie case of lack of enablement for the claim scope as drafted, the arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997). See MPEP 2145 (I).
The rejections are maintained over the claim scope as presently drafted at this time.
B. Applicant requests withdrawal of the rejections under 35 USC §103. Applicant states that nothing in the prior art teaches detecting the frequency of responses of every individual T cell (see pages 17-23 of the 06/19/2026 remarks).
Response: The rejections of the previous office action have been withdrawn and replaced with the substantially modified rejections presented in this Office Action to account for the newly amended claim scope, rendering many of the arguments moot. The claims do not clearly require detecting the responses of every individual T cell. The method is examined based upon its recited active steps and reagents used, where results are deemed to flow necessarily from the sequence of active steps and reagent structures. Thus, where the prior art teaches all recited and required active steps using reagents encompassed within the scope of the claims as drafted, the claims are deemed to be anticipated/made obvious said prior art reference(s). This rationale and rebuttal is deemed to apply to all of Applicant’s arguments which many be deemed to carry over to the rejections for nonobviousness as presented in this Office Action. The rejections presented in this Office Action are deemed to make obvious the instant claims as amended as offering a predictable solution with a reasonable expectation of success.
C. Applicant requests the rejections for double patenting be held in abeyance (see pages 23-24 of the 06/17/2026 remarks).
Response: This has been fully considered but is not found to be persuasive. Applicant’s attention is respectfully directed to M.P.E.P. § 804(I)(B)(1), which states: “A complete response to a nonstatutory double patenting (NSDP) rejection is either a reply by applicant showing that the claims subject to the rejection are patentably distinct from the reference claims or the filing of a terminal disclaimer in accordance with 37 CFR 1.321 in the pending application(s) with a reply to the Office action (see MPEP § 1490 for a discussion of terminal disclaimers). Such a response is required even when the nonstatutory double patenting rejection is provisional.” “As filing a terminal disclaimer, or filing a showing that the claims subject to the rejection are patentably distinct from the reference application’s claims, is necessary for further consideration of the rejection of the claims, such a filing should not be held in abeyance. Only objections or requirements as to form not necessary for further consideration of the claims may be held in abeyance until allowable subject matter is indicated. Replies with an omission should be treated as provided in MPEP § 714.03.Therefore, an application must not be allowed unless the required compliant terminal disclaimer(s) is/are filed and/or the withdrawal of the nonstatutory double patenting rejection(s) is made of record by the examiner.” See MPEP § 804.02, subsection VI, for filing terminal disclaimers required to overcome nonstatutory double patenting rejections in applications filed on or after June 8, 1995. (emphasis added). Accordingly, the rejection is maintained and is expressly not held in abeyance.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Slifka et al (Blood, Vol 90, No 5 (September 1), 1997: pp 2103-2108) teach that immunizing bone marrow donors prior to bone marrow transplant (BMT) has the potential for adoptively transfer ring specific immunity against opportunistic pathogens. Studies have shown that long-term antibody production occurs in the bone marrow and that specific humoral immunity may be transferred from donor to recipient following BMT. However, the magnitude and duration of T-cell memory in the bone marrow compartment has not been adequately investigated. In this study, virus-specific CD8" T-cell responses in the bone marrow were compared with those observed in the spleen of mice acutely infected with lymphocytic choriomeningitis virus (LCMV). During the acute stages of infection, most CD8" T cells in the spleen and bone mar- row showed upregulated surface expression of the activation/memory marker, LFA-1 (LFA-1hi). After clearing LCMV infection, the antiviral immune response subsided to homeostatic levels and the ratio of CD8"/LFA-1hi to CD8"/LFA- 1lo T cells in the spleen and bone marrow of LCMV immune mice returned to the value observed in naive mice (see for example, the abstract).
Ito et al (Cell Immunol. 1995 Jan;160(1):8-13. doi: 10.1016/0008-8749(95)80003-2) teach that the expression of adhesion molecules (LFA-1, ICAM-1, CD29) on T cells activated with cytomegalovirus (CMV) antigen was investigated by three-color flow cytometry analysis. Peripheral blood mononuclear cells (PBMC) from CMV-seropositive adults were cultured with CMV or control antigen for 6 days. After culture, the expression of LFA-1, ICAM-1, and CD29 on T cells in subpopulations defined as CD45RO+ or CD45RO- was analyzed. The population of cells that expressed LFA-1 at high levels (LFA-1high) among CD4+C-D45RO+ cells increased when cultured with CMV antigen compared to control antigen (see for example, the abstract).
Paston (CMV epitope selection and its use in T cell reconstitution in patients undergoing
haematopoietic stem cell transplantation; UMI Number: U593100; obtained from: https://discovery.ucl.ac.uk/id/eprint/1445776/1/U593100%20Redacted.PDF (accessed 08/13/2026)) discuss CMV epitope selection and its use in T cell reconstitution.
Peggs et al (Blood. 2002 Jan 1;99(1):213-23. doi: 10.1182/blood.v99.1.213.) teach that Under conditions of impaired T-cell immunity, human cytomegalovirus (HCMV) can reactivate from lifelong latency, resulting in potentially fatal disease. A crucial role for CD8+ T cells has been demonstrated in control of viral replication, and high levels of HCMV-specific cytotoxic T-lymphocytes are seen in immunocompetent HCMV-seropositive individuals despite very low viral loads. Elucidation of the minimum portion of the anti-HCMV T-cell repertoire that is required to suppress viral replication requires further study of clonal composition. he specificity and clonal composition of the CD8+ T-cell responses were evaluated using HLA tetrameric complexes and T-cell receptor β chain (TCRBV) spectratypic analyses. There was a skewed reactivity toward the matrix protein pp65, with up to 40-fold expansion of CD8+ T cells directed toward a single peptide-MHC combination. Individual expansions detected on TCRBV spectratype analysis were HCMV-specific and composed of single or highly restricted numbers of clones. There was preferential TCRBV gene usage (BV6.1/6.2, BV8, and BV13 in HLA-A*0201+ individuals) but lack of conservation of CDR3 length and junctional motifs between donors. While there was a spectrum of TCR repertoire diversity directed toward individual MHC-peptide combinations between donors, a relatively small number of clones appeared to predominate the response in each case. These data provide further insight into the range of anti-HCMV responses and will aid the design and monitoring of adoptive immunotherapy protocols (see for example, the abstract).
Arrol et al (Clinical and Experimental Immunology, 153: 86–95; doi:10.1111/j.1365-2249.2008.03677.x), US 20140120557 A1 (citation 5 under US Patent/PGPub on the06/10/2024 IDS), Diener et al (Acta Biomaterialia 8 (2012) 99-107; citation 6 under the Non-Patent Literature heading of the 06/10/2024 IDS), Huse et al (Immunity 27, 76-88, July 2007 Elsevier Inc; citation 9 under the Non-Patent Literature heading of the 06/10/2024 IDS), Christo et al (Immunology and Cell Biology (March 2015) 93, 694–704; doi:10.1038/icb.2015.34), Christo (Aust. J. Chem. 2012, 65, 45-49, http;//dx.doi.org/10.1071/CHl 1311), WO 2015017889 A1 (Citation 1 under Foreign Patent Documents on the 06/10/2024 IDS), US 20110123994 A1, US 20070178532 A1, and Wulfing et al (J Exp Med. 1997 May 19;185(10):1815-25. doi: 10.1084/jem.185.10.1815) continue to be deemed relevant.
Additionally, Schmittnaegel et al (Cancer Immunol Res. 2015 Jul;3(7):764-76. doi: 10.1158/2326-6066.CIR-15-0037. Epub 2015 Feb 17) teach that, in particular, memory CD8+ T cells play a major role in host defense by rapid recognition and lysis of virus-infected cells. CMV infects much of the population, existing in a viral latency stage where viral reactivation is kept in check by the immune system, but in immunocompromised patients and neonates such viral reactivation has a substantial influence on the number and the distribution of various T-cell subsets, especially CD8+ T cells. CMV-specific CD8+ T cells are believed to play an essential role in the defense against CMV, and a correlation is observed between a higher percentage of CMV-specific CD8+ T cells and more effective control of the virus. CMV-specific CD8+ T cells were isolated from PBMC preparations (see for example, pages 764-765).
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.
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/Ashley Gao/
Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678
Prosecution Insights