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 .
Status of Claims
Claims 1-9 and 11-15 are pending.
Priority
Claims 1-9 and 11-15 are a 371 of PCT/JP 2022/019563 filed on May 6, 2022, which has priority to foreign application JAPAN 2021-079296 filed on May 7, 2021.
Information Disclosure Statement
The information disclosure statement(s) (IDS) submitted on November 2, 2023, and on December 11, 2023, were filed before the mailing of the First Office Action on January 31, 2026. The Non-Patent Literature is in compliance with the provisions of 37 CFR 1.97 and are being considered by the examiner.
Drawings
The drawings are objected to because:
Figures 1-10 – the X and Y axis labeling is not legible.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
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.
Claims 1-9 and 11-15 are rejected under 35 U.S.C. §103 as being unpatentable over Reed & Wetzel (Hereinafter Reed) [CD4+ T cell differentiation and activation, Methods Mol Biol., 2018], in view of Tao et al. [Hypoxia-inducible factors in T lymphocyte differentiation and function. A review in the theme: cellular responses to hypoxia, Am J Physiol Cell Physiol, 2015], in view of Li et al. [Age related human T cell subset evolution and senescence, Immunity & Aging, 2019], in view of Olteanu et al. [Time and temperature stability of T cell subsets evaluated by dual platform method, Am J Blood Res, 2012], in view of Daniels & Teixeiro (Hereinafter Daniels) [The persistence of T cell memory, Cell Mol Life Sci, 2010], in view of Rush & Hodgkin (Hereinafter Rush) [B cells activated via CD40 and IL-4 undergo a division burst but require continued stimulation to maintain division, survival and differentiation, European Journal of Immunology, 2001], in view of Avery et al. [BAFF selectivity enhances the survival of plasmablasts generated from human memory B cells, J Clin Invest., 2003], in view of Bates [Culturing cells under hypoxic conditions for biologically relevant results, American Laboratory, 2012], in view of Baboo et al. [The impact of varying cooling and thawing rates on the quality of cryopreserved human peripheral blood T cells, Scientific Reports, 2019].
For claim 1, Reed, discussing CD4+ T cell activation and differentiation, discloses a method for activating naïve T cells that include a memory formation step for the activated T cells where the differentiation-inducing factor is absent after the activation step [Abstract, 2. Materials, Establishing Polarization Controls]. However, Reed does not teach the step of culturing T cells in a hypoxic environment in the memory formation step.
However, Tao et al., discussing cellular responses to hypoxia, discloses the use of hypoxia given that low oxygen, i.e. hypoxia, is a common trait of inflamed tissues [Abstract]. Furthermore, culturing in hypoxic conditions is a better reflection of natural physiological conditions since hypoxia also plays a role in inducing or promoting differentiation of activated T cells [Fig. 1, Introduction ¶ 4].
For claim 2, Tao et al. also teaches that hypoxic environments contain an oxygen concentration between 0.5% to 5% given that inflamed tissues can often reach oxygen levels as low as 0.5% to 3% [Introduction ¶ 4]. Based on this, it would have been prima facie obvious prior to the filing of the claimed invention to modify the systems and methods of Reed where the authors discussed methods for activating, differentiating, and maintaining T cell cultures with the additional teachings of Tao et al. that discloses that hypoxic environments use for culturing T cells better represent a more natural environment since hypoxia can promote differentiation of activated T cells and better represents or mimics inflamed tissue. Because of this, there is a reasonable expectation of success that a person of ordinary skill would recognize the teachings of both Reed and Tao et al. as a means of activating, differentiating, and culturing T cells in a hypoxic environment.
For claim 3 where similar to claim 1, the T cells are exposed or subjected to a stress treatment, Reed, discussing CD4+ T cell activation and differentiation, discloses a method for activating naïve T cells that include a memory formation step for the activated T cells where the differentiation-inducing factor is absent after the activation step [Abstract, 2. Materials, Establishing Polarization Controls]. However, Reed does not teach naïve T cells being exposed to a stress treatment where the stress treatment is performed on activated T cells before the memory-formation step. However, Daniels discloses mTOR could be used as a stress treatment on certain T cells given it can influence T cell differentiation, particularly the T-bet/Eomes transcription factor balance where it is capable of directing CD8 cells, i.e. T cells, toward memory vs. effector phenotypes [Signals required for CD8 T cell memory differentiation ¶ 5].
For claim 4 where the naïve T cells have been kept in 0˚C to 10˚C for one hour or longer, Olteanu et al., discussing time and temperature stability of T cells, discloses that T cells can be stored, including naïve T cells, at around 4˚C for up to 96 hours [Methods ¶ 1, Results ¶ 1]. Based on this, it would have been prima facie obvious to a person of ordinary skill prior to the filing of the claimed invention to modify the systems and methods of Reed where the authors discussed methods for activating, differentiating, and maintaining T cell cultures with the additional teachings of with Olteanu et al. that discloses refrigerating T cells for up to 96 hours. Therefore, there is a reasonable expectation of success that a person of ordinary skill would have known to combine the teachings of Reed with the further teachings of Olteanu et al. in order to properly store T cells, including naïve T cells, at specified temperatures for periods that include more than one hour up to 96 hours.
For claim 5 where the naïve T cells are collected from humans above 50, Li et al., where the authors discuss different subsets of T cells found in patients based on age, teaches that naïve T cells can be obtained from humans aged 50 years or older where the naïve T cells retain the capacity for proliferation and differentiation into memory T cells [Fig. 1].
For claim 6 where the memory-formation step is performed after the activated T cells are frozen and thawed, Baboo et al., discussing the impact of varying cooling and thawing rates on the quality of cryopreserved blood T cells, discloses that clinical delivery of immunotherapies, including T cell treatments, include cryopreserved and thawed T cell populations and provides examples on how to perform these freeze/thaw methods [Abstract]. Additionally, freezing and thawing T cells after activation is a routine practice that preserves activation status, enables flexible scheduling and transport, and allows for maintaining consistent phenotypes. Furthermore, it can also act as a mild stressor capable of influencing memory differentiation.
For claim 7 where the manufacturing method of memory T cells where the naïve T cells are CD4+ T cells, Reed discloses the T cells that are activated and differentiated are CD4+ T cells [Abstract].
For claim 8 where the CD4+ T cells are CD4+ Th1 cells, Reed also discloses that the CD4+ T cells are both Th1 and Th2 cells [Fig.’s 1 & 2].
For claim 9 where the total number of living cells include memory T cells, central memory T cells, stem cell memory T cells, and effector memory T cells is equal to or greater than 20% of the total number of living cells, a person of ordinary skill, following standard activation and memory formation protocols would be able to arrive at a percentage where stem cell T cells, central memory T cells, and effector memory T cells make up at least 20% of the total number of living memory T cells. This could be achieved through routine analysis using flow cytometry or similar assays. Additionally, an artisan would understand that the proportion of stem cell memory, central memory, and effector memory T cells could also be adjusted through culture conditions, cytokine selection, or subset enrichment making it further routine for a person of ordinary skill to arrive a total living cell concentration where certain memory T cells make up at least 20% of the total living cell population.
For claim 11 where, similar to claim 1, B cells are cultured in a similar manner, Rush, discussing B cell activation, teaches the activation and subsequent culture of naïve B cells using differentiation-inducing factors such as CD40 and IL-4 [Abstract]. Additionally, Avery et al., where it is disclosed that other factors, independent of differentiation stimuli, can be used for modulating B cell viability [Abstract]. Furthermore, Bates, discussing culturing cells in hypoxic conditions, teaches that immune cells cultured in at low oxygen behaved as they were in a healthy body [Use of hypoxic conditions yield better results ¶ 2].
Here, it would have been prima facie obvious to a person of ordinary skill in the art prior to the filing of the claimed invention to modify the systems and methods of Rush were B cells were activated with CD40 and IL-4 with the further teachings of Avery et al. that discloses other factors, aside from differentiation factors, can be used for inducing proliferation with the additional teachings of Bates that taught low oxygen environments for immune cells causes cultured cells to behave as though they were in the body. Given this, there is a reasonable expectation of success that a person of ordinary skill in the art would recognize the teachings of Rush combined with both Avery et al. and Bates where a method for manufacturing naïve B cells were exposed to an activation and differentiation-inducing factor where afterwards the activated B cells were placed in a hypoxic environment as a means for obtaining the long-term viability acquisition step that did not include the use of an additional differentiation-inducing factor.
For claim 12 where the types of B cells include germinal center B cells, it would have been prima facie obvious to a person of ordinary skill to use germinal center B cells which are already activated, proliferation-primed, and differentiation committed, in place of naïve B cells given that these cells naturally give rise to memory B cells and are capable of surviving in culture with standard survival factors.
For claim 13 where the naïve T cells are naïve CD4+ T cells or naïve CD8+ cells, Reed discloses the use of CD4+ T cells, as well as, their subsets that include Th1 and Th2 [Introduction ¶ 1-2].
For claim 14 where the differentiating-inducing factor is for CD4+ T cells into Th1 CD4+ T cells, Reed discloses the use of xenobiotics as a means of activation for obtaining Th1 and Th2 CD4+ T cell subsets [Introduction ¶ 1-2].
For claim 15, which depends on claim 3, where the total number of living cells include memory T cells, central memory T cells, stem cell memory T cells, and effector memory T cells is equal to or greater than 20% of the total number of living cells, a person of ordinary skill, following standard activation and memory formation protocols would be able to arrive at a percentage where stem cell T cells, central memory T cells, and effector memory T cells make up at least 20% of the total number of living memory T cells. This could be achieved through routine analysis using flow cytometry or similar assays. Additionally, an artisan would understand that the proportion of stem cell memory, central memory, and effector memory T cells could also be adjusted through culture conditions, cytokine selection, or subset enrichment making it further routine for a person of ordinary skill to arrive a total living cell concentration where certain memory T cells make up at least 20% of the total living cell population.
The Supreme court has acknowledged:
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 varition..103 likely bars its patentability…if a technique has been used to improve one device, and a person of ordinary skill in the art would recognize that it would improve similar devices in the same way, using the technique is obvious unless its actual application is beyond that person’s skill. A court must ask whether the improvement is more than the predictable use of prior-art elements according to their established functions…
…the combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results (see KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 U.S. 2007) emphasis added.
In KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398 (2007), the Supreme Court reaffirmed "the conclusion that when a patent 'simply arranges old elements with each performing the same function it had been known to perform' and yields no more than one would expect from such an arrangement, the combination is obvious." Id. at 417 (quoting Sakraida v. Ag Pro, Inc., 425 U.S. 273,282 (1976)). The Supreme Court also emphasized a flexible approach to the obviousness question, stating that the analysis under 35 U.S.C. § 103 "need not seek out precise teachings directed to the specific subject matter of the challenged claim, for a court can take account of the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at 418; see also id. at 421 ("A person of ordinary skill is... a person of ordinary creativity, not an automaton.").
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Conclusion
No claims allowed.
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/JOHN DAVID MOORE/Examiner, Art Unit 1638
/ROBERT M KELLY/Primary Examiner, Art Unit 1638