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 .
Claim Status
Claims 1-27 are pending and currently under consideration for patentability under 37 CFR 1.104.
Priority
This application claims benefit of Provisional U.S. Application No. 63/438,458 filed on 1/11/2023. 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.
Claims 1-27 have an effective filing date of 1/11/2023 corresponding to Provisional U.S. Application No. 63/438,458.
Information Disclosure Statement
The information disclosure statement(s) filed on 04/04/2024 has/have been considered. Signed copies are enclosed.
Drawings
The drawings are objected to because Fig. 6B refers to red and green colors to indicate CD4, CD49a, and CD103 expression in black and white images of biopsy samples. 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 Objections
Claim 23 is objected to because of the following informalities: “aTIM-3+” should read “a TIM-3+”. Claim 26 is objected to because of the following informalities: “CD49a-CD4+” should read “CD49a-CD4+”. Appropriate correction is required.
Claim Rejections - 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.
Claims 1-19 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for the methods of (i) halting progression and lessening the symptoms of idiopathic pulmonary fibrosis in a subject in need thereof comprising administering a composition comprising a CD49a+CD4+ T resident memory cell (instant claim 1) and (ii) increasing a proportion of CD49a+CD4+ to CD103+CD4+ cell phenotypes in the lungs of a subject in need thereof comprising administering a composition comprising a CD49a+CD4+ T resident memory cell (instant claim 19), does not reasonably provide enablement for methods of (i) curing, preventing, halting progression, and lessening the symptoms of all fibrosis in a subject in need thereof comprising administering a composition comprising any T resident memory cell (instant claim 1) and (ii) increasing a proportion of CD49a+CD4+ to CD103+CD4+ cell phenotypes in any tissue of a subject in need thereof comprising administering a composition comprising a CD49a+CD4+ T resident memory cell (instant claim 19). The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
As a general rule, enablement must be commensurate with the scope of claim language. MPEP 2164.08 states, “The Federal Circuit has repeatedly held that “the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation’.” In re Wright, 999 F.2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)” (emphasis added). The “make and use the full scope of the invention without undue experimentation” language was repeated in 2005 in Warner-Lambert Co. v. Teva Pharmaceuticals USA Inc., 75 USPQ2d 1865, and Scripps Research Institute v. Nemerson, 78 USPQ2d 1019 asserts: “A lack of enablement for the full scope of a claim, however, is a legitimate rejection.” The principle was explicitly affirmed most recently in Auto. Tech. Int’l, Inc. v. BMW of N. Am., Inc., 501 F.3d 1274, 84 USPQ2d 1108 (Fed. Cir. 2007), Monsanto Co. v. Syngenta Seeds, Inc., 503 F.3d 1352, 84 U.S.P.Q.2d 1705 (Fed. Cir. 2007), and Sitrick v. Dreamworks, LLC, 516 F.3d 993, 85 USPQ2d 1826 (Fed. Cir. 2008). See also In re Cortright, 49 USPQ2d 1464, 1466 and Bristol-Myers Squibb Co. v. Rhone-Poulenc Rorer Inc., 49 USPQ2d 1370.
The factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have been described in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988). Among these factors are: (1) the nature or the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary. When the above factors are weighed, it is the examiner’s position that one skilled in the art could not practice the invention without undue experimentation. Some experimentation is not fatal; the issue is whether the amount of experimentation is “undue”; see In re Vaeck, 20 USPQ2d 1438, 1444.
(1) The nature of the invention, (2) the state of the prior art, (3) The relative skill of those in the art, (4) the predictability or unpredictability of the art, and (5) the breadth of the claims
Instant claim 1 is drawn to “[a] method of treating fibrosis in a subject in need thereof comprising administering to the subject a composition comprising a T resident memory (TRM) cell, thereby treating the fibrosis” (lines 1-3). Instant claim 19 is drawn to “[a] method of increasing a proportion of CD49a+CD4+ to CD103+CD4+ cell phenotypes in a tissue of a subject in need thereof comprising administering to the subject, a composition comprising a CD49a+CD4+ TRM cell to the subject, thereby increasing the proportion of CD49a+CD4+ to CD103+CD4+ cell phenotypes in a tissue of the subject” (lines 1-4).
The instant specification states:
“the term ‘tissue resident memory T cell’ (TRM cell) denotes lymphocyte cells capable of occupying nonlymphoid tissues without recirculating” (¶ 0028);
“the term ‘fibrosis’ refers to fibrous tissue formation beyond levels observed in healthy tissues” (¶ 0036); and
“[t]he term ‘treatment’… refers to 1) therapeutic treatments or measures that cure, slow down, lessen symptoms of, and/or halt progression of a diagnosed pathologic conditions or disorder, and/or 2) prophylactic/preventative measures” (¶ 0039).
In view of the definitions given in the instant specification, instant claims 1 and 19 are incredibly broad and drawn to (i) a method of curing, preventing, halting progression, and lessening the symptoms of all fibrosis in a subject in need thereof comprising administering a composition comprising any T resident memory cell (instant claim 1) and (ii) a method of increasing a proportion of CD49a+CD4+ to CD103+CD4+ cell phenotypes in any tissue of a subject in need thereof comprising administering a composition comprising a CD49a+CD4+ T resident memory cell (instant claim 19), the full scope of which is not enabled by the methods as instantly claimed (the nature of the invention and the breadth of the claims).
This invention is in a class of invention which the CAFC has characterized as "the unpredictable arts such as chemistry and biology". Mycogen Plant Sci., Inc. v. Monsanto Co., 243 F.3d 1316, 1330 (Fed. Cir. 2001). The dependent claims demonstrate that practicing the claimed invention encompasses numerous variables. For example, dependent claims recite T resident memory cell phenotypes (instant claims 2-5), where the T resident memory cell is derived (instant claim 6), genes upregulated in the T resident memory cell upon administration (instant claims 7-9), the type of fibrosis (instant claims 10-12), administrative parameters (instant claims 13-16), and how the resident memory cell is generated (instant claims 17-18).
Collectively, the dependent claims demonstrate that the invention is directed to a method for treatment of fibrosis in a subject or a method of increasing a proportion of CD49a+CD4+ to CD103+CD4+ cell phenotypes in a tissue of a subject, subject matter that is highly complex and unpredictable, wherein therapeutic efficacy depends on (i) the T resident memory cell phenotype (linked to the tissue it is derived from and how it is generated), (ii) the type of fibrosis, and (iii) the dose and route of the administered treatment.
The following details the state of the prior art concerning fibrosis treatment and T resident memory cells as instantly claimed:
Tissue resident memory T cells
Kumar et al. (Human Tissue-Resident Memory T Cells Are Defined by Core Transcriptional and Functional Signatures in Lymphoid and Mucosal Sites, Cell Reports, 2017) teach tissue resident memory T cells exist is a variety of tissues including “lungs, intestines, skin, liver, brain, and other mucosal surfaces” (Pg. 1, column 1, last ¶, second to last line). Kumar et al. further teach phenotypic markers for these cells such as CD69, CD103, CD4, and CD8 (Pg. 1, column 2, entire ¶ 2). These teachings indicates the location and phenotype of tissue resident memory T cells create distinct cell populations.
Rahimi et al. (Distinct functions of tissue-resident and circulating memory Th2 cells in allergic airway disease, J Exp Med, 2020) teach tissue resident memory CD4+ T cells from the lung have higher transcript levels of ECM organization proteins such as Col1a1, Col1a2, and Dcn compared to circulating memory CD4+ T cells (Fig. 5E, heatmap of genes known to be involved in ECM biology in the two cell types). Rahimi et al. further teach “regulation and interaction with the ECM may play an important role in the development, maintenance, and function of [tissue resident memory T] cells in various tissues” (Pg. 10, column 2, ¶ 2, lines 24-26). This teaching indicates certain subsets of tissue resident memory T cells would be beneficial in a therapeutic approach due to their unique transcriptional profile. Therefore, instant claims 1 and 19 are extremely broad due to the vast number of tissue resident memory T cell subpopulations encompassed, based on tissue localization and/or cell surface markers, each with their own transcriptional signature that can be harnessed for targeted immunotherapies.
The instant specification states CD49a+CD4+ T resident memory cells were administered intratracheally to the lung in an idiopathic pulmonary fibrosis mouse model (Example 1, Materials and Methods, ¶ 0086). Therefore, the instant specification provides support for the use of CD49a+CD4+ T resident memory cells, administered specifically to the lung.
Fibrosis
While the state of the art is relatively high with regard to the treatment of specific types of fibrosis, the state of the art with regard to treating fibrosis broadly is underdeveloped. Rosenbloom et al. (Human Fibrotic Diseases: Current Challenges in Fibrosis Research, Methods Mol Biol, 2017) teach “[v]irtually every organ in the human body can be affected by physiologic and pathologic fibrotic reactions” (Pg. 1, last ¶, lines 1-2) including “multi-system diseases such as systemic sclerosis (SSc) and nephrogenic systemic fibrosis, as well as fibrotic disorders affecting individual organs including the pulmonary, kidney, liver, cardiac, and bladder” (Pg. 2, ¶ 1, lines 9-12) This teaching indicates fibrosis is not a single disease but rather a diverse group of diseases affecting various organs. Therefore, instant claim 1 is extremely broad due to the vast number of possible fibrotic diseases encompassed by the term “fibrosis.”
Furthermore, Rosenbloom et al. state “[b]ecause of the complex pathogenesis and the extreme redundancy of the pathways involved, it is unlikely that any single drug will be successful in arresting or modifying the progression of major fibrotic diseases” (Pg. 15, ¶ 1, lines 4-8). This teaching indicates there is no known fibrotic treatment that is effective against all types of fibrosis. Accordingly, the treatment of all fibrosis remains an unpredictable field in which efficacy cannot be readily extrapolated across different types of fibrosis as there is no universally effective treatment.
A curative or preventative treatment for all fibrosis is not known. For example, Sellers and Maqbool (Cystic Fibrosis [CF], GI Kids, 2021) teach cystic fibrosis is a genetic disorder and thus there is no way to prevent it (Pg. 4, under “Can cystic fibrosis be prevented?” heading, line 1) and the National Health Service (Treatment: Idiopathic pulmonary fibrosis, 2022) teaches “[t]here’s currently no cure for idiopathic pulmonary fibrosis (IPF). The main aim of treatment is to relieve the symptoms as much as possible and slow down its progression” (Pg. 1, ¶ 1, lines 1-2). These teachings indicate it is not possible to cure or prevent all fibrosis. Therefore, the instant specification’s definition of “treatment” is extremely broad due to its inclusion of curing, preventing, halting progression, and lessening the symptoms of fibrosis, not all of which are supported.
The instant application teaches CD49a+CD4+ T resident memory cells “are capable of halting and even reversing the development of pulmonary fibrosis” (Example 4, ¶ 0101) and increases the CD49a+CD4+/CD103+CD4+ ratio (Example 7, ¶ 0112) in an idiopathic pulmonary fibrosis mouse model. Therefore, the instant specification provides support for CD49a+CD4+ T resident memory cells (i) halting progression and lessening the symptoms of idiopathic pulmonary fibrosis in a subject and (ii) increasing a proportion of CD49a+CD4+ to CD103+CD4+ cell phenotypes in the lungs of a subject.
For a person having ordinary skill in the art, i.e. someone with a PhD and/or MD (the relative skill of those in the art), the predictability of applying (i) any T resident memory cell to cure, prevent, halt the progression, and alleviate all fibrosis (instant claim 1) and (ii) a CD49a+CD4+ T resident memory cell to increase the CD49a+CD4+/CD103+CD4+ ratio in any tissue (instant claim 19) would be low (the predictability or unpredictability of the art) given that:
T resident memory cells can localize in various tissues, present an multitude of cell surface markers, and have unique transcriptional profiles (see Kumar et al. and Rahimi et al. in the state of the prior art). The use of any T resident memory cell in targeted immunotherapies would be unpredictable given their various presentations.
Fibrosis is not a single disease but rather a diverse group of diseases affecting various organs; currently, there is no known treatment for all fibrosis (see Rosenbloom et al. in the state of the prior art). Furthermore, all fibrosis is not known to be curable nor preventable (see Sellers and Maqbool and National Health Service in the state of the prior art). A generic treatment, including a curative or preventative treatment, for all fibrosis would not predictably be effective.
Consequently, instant claims 1 and 19 are directed to complex and unpredictable fields, where the successful treatment of all fibrosis or increasing the CD49a+CD4+/CD103+CD4+ ratio in any tissue cannot be readily extrapolated from the limited number of disclosed examples in the instant application. Evidence of efficacy of CD49a+CD4+ T resident memory cells (i) halting progression and lessening the symptoms of idiopathic pulmonary fibrosis in a subject and (ii) increasing a proportion of CD49a+CD4+ to CD103+CD4+ cell phenotypes in the lungs of a subject is provided in the instant specification.
Therefore, the methods of (i) halting progression and lessening the symptoms of idiopathic pulmonary fibrosis in a subject in need thereof comprising administering a composition comprising a CD49a+CD4+ T resident memory cell (instant claim 1) and (ii) increasing a proportion of CD49a+CD4+ to CD103+CD4+ cell phenotypes in the lungs of a subject in need thereof comprising administering a composition comprising a CD49a+CD4+ T resident memory cell (instant claim 19) is supported. The methods of (i) curing, preventing, halting progression, and lessening the symptoms of all fibrosis in a subject in need thereof comprising administering a composition comprising any T resident memory cell (instant claim 1) and (ii) increasing a proportion of CD49a+CD4+ to CD103+CD4+ cell phenotypes in any tissue of a subject in need thereof comprising administering a composition comprising a CD49a+CD4+ T resident memory cell (instant claim 19) is not supported.
(6) The amount of direction or guidance presented, (7) the presence or absence of working examples, and (8) the quantity of the experimentation
The instant application teaches CD49a+CD4+ T resident memory cells “are capable of halting and even reversing the development of pulmonary fibrosis” (Example 4, ¶ 0101) and increases the CD49a+CD4+/CD103+CD4+ ratio (Example 7, ¶ 0112) in an idiopathic pulmonary fibrosis mouse model. CD49a+CD4+ T resident memory cells were administered intratracheally to the lung in an idiopathic pulmonary fibrosis mouse model (Example 1, Materials and Methods, ¶ 0086). Therefore, the instant specification provides support for CD49a+CD4+ T resident memory cells (i) halting progression and lessening the symptoms of idiopathic pulmonary fibrosis in a subject and (ii) increasing a proportion of CD49a+CD4+ to CD103+CD4+ cell phenotypes in the lungs of a subject.
The specification does not provide any additional examples or guidance on how to use T resident memory cells with phenotypes other than CD49a+CD4+ to (i) treat fibrosis besides idiopathic pulmonary fibrosis or (ii) increase the CD49a+CD4+/CD103+CD4+ ratio in a tissue besides the lung as recited in instant claims 1 and 19 (the amount of direction or guidance presented and the presence or absence of working examples). The specification of the instant application does not provide support for the entire scope of the claims.
T resident memory cells can localize in various tissues, present an multitude of cell surface markers, and have unique transcriptional profiles (see Kumar et al. and Rahimi et al. in the state of the prior art). As T resident memory cells have substantial phenotypic and tissue-specific heterogeneity, identifying which T resident memory cells to use in a therapeutic approach would require extensive screening and testing.
Fibrosis is not a single disease but rather a diverse group of diseases affecting various organs; currently, there is no known treatment for all fibrosis (see Rosenbloom et al. in the state of the prior art). Furthermore, all fibrosis is not known to be curable nor preventable (see Sellers and Maqbool and National Health Service in the state of the prior art). Therefore, even for a given T resident memory cell subpopulation, it is not readily established which fibrotic diseases (if any) could be treated with said cell, including curative or preventative treatments.
The amount of experimentation would not be reasonable because it would require determining which T resident memory cells, specifically their cell phenotype and tissue localization, to use for any and all fibrosis treatment or increasing the CD49a+CD4+/CD103+CD4+ ratio in any and all tissues in a subject; this is not routine and would therefore require undue experimentation (the quantity of the experimentation, see MPEP 2164.06).
Instant claims 1 and 19 are not enabled because a person having ordinary skill in the art as of the effective filing date of the application would not be able to use (i) any T resident memory cell to cure, prevent, halt the progression, and alleviate all fibrosis (instant claim 1) and (ii) a CD49a+CD4+ T resident memory cell to increase the CD49a+CD4+/CD103+CD4+ ratio in any tissue (instant claim 19) with a predictability of success for the reasons outlined above. Instant claims 2-18 are included in this rejection as they incorporate and/or depend on instant claim 1.
Claim Rejections - 35 USC § 112(b)
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.
Claims 15-16 and 24-27 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The term “about” in claims 15-16 and 27 is a relative term which renders the claims indefinite. The term “about” is not defined by the claims, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The use of “about” renders the amount of cells (claims 15 and 27) and the duration between doses (claim 16) indefinite.
The instant specification states “the term ‘about’ in association with a numerical value is meant to include any additional numerical value reasonably close to the numerical value indicated” (¶ 0026, emphasis added). However, the instant specification does not give objective and clear standards for what is a reasonably close numerical value. Therefore, the term “about” is still indefinite despite the given definition as a person having ordinary skill in the art would not understand the metes and bounds of the claims and the rejection still applies.
For the purposes of claim interpretation, “about” will be considered as ±10% the given numerical value and/or range.
Regarding claims 24-26, the phrases “upregulated” (claims 24-25) and “downregulated” (claim 26) render the claims indefinite because no baseline or reference is provided from which the genes are upregulated or downregulated, making them subjective terms. MPEP 2173.06(b) states: “Some objective standard must be provided in order to allow the public to determine the scope of the claim. A claim term that requires the exercise of subjective judgment without restriction may render the claim indefinite. In re Musgrave, 431 F.2d 882, 893, 167 USPQ 280, 289 (CCPA 1970).” The instant specification does not provide an objective standard for the phrases “upregulated” and “downregulated” and thus they are indefinite. Claim 7 is not included in this rejection as it establishes a reference from which genes are upregulated i.e. following administration of the tissue resident memory T cells to the subject.
For the purposes of claim interpretation, the phrases “upregulated” and “downregulated” will be treated as the genes are upregulated and downregulated respectively following administration of the tissue resident memory T cells to the subject.
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.
Claims 1, 3-6, 10-14, 16-17, 20, and 22-23 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by US20210355443A1 (filed 2019-10-18, published 2021-11-18; hereinafter referred to as US ‘443) as evidenced by WebMD (Johnston, 2025, pgs. 1-4; WebMD, Saline (Sodium Chloride) for Nebulization - Uses, Side Effects, and More).
.
Note: T resident memory cell and tissue resident memory T cell are used interchangeably in this office action.
Regarding instant claims 1 and 10-12, US ‘443 teaches “methods of using the tissue resident memory T cells as adoptive cell therapy” (Abstract; instant claim 1) wherein the method (i) treats a subject with an autoimmune disease, specifically “idiopathic pulmonary fibrosis” (¶ 0076; instant claims 1 and 10-12) and (ii) uses “pharmaceutical compositions and formulations comprising [tissue resident memory T] cells” (¶ 0094; instant claim 1). This teaching reads on a method of treating fibrosis in a subject comprising administering a composition comprising a T resident memory cell (instant claim 1), wherein the fibrosis is lung fibrosis (instant claims 10-11), specifically idiopathic pulmonary fibrosis (instant claim 12).
Regarding instant claims 3-5, 20, and 22-23, US ‘443 further teaches the pharmaceutical composition comprises “a pharmaceutically acceptable carrier” (¶ 0094) wherein the pharmaceutical carrier is “in the form of aqueous solutions, such as normal saline ” (¶ 0095; instant claim 20). US ‘443 does not explicitly teach saline is suitable for inhalation or nebulization. However, WebMD states “[s]aline for nebulization is commonly used” (Pg. 1, under “What is saline for nebulization used for?” heading, line 1) and that nebulization “allows you to breathe it into your lungs” (Pg. 1, under “How does saline for nebulization work (mechanism of action)?”, line 1). Therefore, the saline is inherently a carrier suitable for inhalation or nebulization as evidenced by WebMD (instant claim 20). US’ 443 further teaches a tissue resident memory cell population is CD49a+CD69+CD103- (Fig. 3C, rightmost plot, expression of tissue resident memory T cell markers assessed shows CD49a+CD69+CD103- cells; instant claims 3-5, 20, and 22-23). These teachings read on a pharmaceutical composition comprising a T resident memory cell formulated in a carrier suitable for inhalation or nebulization (instant claim 20), the T resident memory cell is CD49a+ (instant claims 3 and 20), the T resident memory does not express CD103 (instant claims 4 and 22), and the T resident memory cell is a CD69+ cell (instant claims 5 and 23).
Regarding instant claims 6 and 17, US ‘443 further teaches the tissue resident memory T cells were generated by activating peripheral mononuclear blood cells from human donors with anti-CD3/anti-CD28 beads and IL-2 (Example 2, Materials and Methods, entire ¶ 0103). This teaching reads on the T resident memory cell is derived from the subject (instant claim 6) and said cells are generated by contacting a peripheral blood mononuclear cell (PBMC) with a CD3 antibody, a CD28 antibody, and IL-2 (instant claim 17).
Regarding instant claims 13-14 and 16, US ‘443 further teaches the tissue resident memory T cells are administered “intratracheally” (claim 115 of US ‘443; instant claims 13-14) and multiple times with 1-7 days between doses (¶ 0075, “one or more doses of the cells.. the duration between doses is 1, 2, 3, 4, 5, 6, 7, or more days”; instant claim 16). These teachings read on intratracheal administration (instant claims 13-14) and repeating the administration after about 1-400 days (instant claim 16).
US ‘443 further teaches “a therapeutically effective amount of immune cells can vary from about 5×106 cells per kg [body weight]… The exact amount of immune cells is readily determined by one of skill in the art based on the age, weight, sex, and physiological condition of the subject” (¶ 0082). This teaching gives motivation for optimizing the exact dosage of cells.
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 2, 7-9, 19, 21, and 24-26 are rejected under 35 U.S.C. 103 as being unpatentable over US20210355443A1 (filed 2019-10-18, published 2021-11-18; hereinafter referred to as US ‘443) in view of Rahimi et al. (Distinct functions of tissue-resident and circulating memory Th2 cells in allergic airway disease, J Exp Med, 2020 Sep 7, 217(9):e20190865) as evidenced by WebMD (Johnston, 2025, pgs. 1-4; WebMD, Saline (Sodium Chloride) for Nebulization - Uses, Side Effects, and More) and Collins et al. (Adoptive transfer of CD49a+ Tissue resident memory cells reverses pulmonary fibrosis in mice, bioRxiv [Preprint], 2024 Mar 14:2024.03.13.584814).
The ’443 and WebMD references are as discussed above and incorporated by reference herein.
As fully described in the 102 rejection section, US ‘443 teaches a method for treating fibrosis in a subject comprising administering a composition comprising a T resident memory cell (instant claim 1) and a pharmaceutical composition comprising said cell and a carrier suitable for inhalation or nebulization (instant claim 20).
US ‘443 does not teach (i) the specific genes (instant claims 8-9 and 24-25) upregulated in a tissue resident memory CD4+ T cell (instant claims 2 and 21) following administration to the subject (instant claim 7), (ii) increasing a proportion of CD49a+CD4+ to CD103+CD4+ cell phenotypes in a tissue of a subject (instant claim 19), and (iii) the expression of IL17a and/or PD-1 in CD49a-CD4+ vs CD49a+CD4+ cell populations (instant claim 26).
Rahimi et al. teach genes expressed in circulating memory CD4+ T cells vs. tissue resident memory CD4+ T cells, specifically from the lung (Fig. 5; Pg. 7, column 2, last ¶, last 2 lines, “YFP−ST2+CD4+ T cells from the lung parenchyma and secondary lymphoid organs [SLO]” i.e. circulating cells). Regarding instant claims 2, 8-9, 21, and 24-25, Rahimi et al. further teach tissue resident memory CD4+ T cells (instant claim 2) from the lung have higher transcript levels of ECM organization proteins (instant claims 8 and 24) such as Col1a1, Col1a2, and Dcn (instant claims 9 and 25) compared to circulating memory CD4+ T cells (Fig. 5E, heatmap of genes known to be involved in ECM biology in the two cell types). This teaching indicates tissue resident memory CD4+ T cells (instant claims 2 and 21) located in the lung express a characteristic gene expression profile including extracellular matrix organization proteins (instant claims 8 and 24) such as Col1a1, Col1a2, and Dcn (instant claims 9 and 25).
Consequently, regarding instant claim 7, once tissue resident memory CD4+ T cells are inhaled and engraft in the lung, they would be expected to exhibit the characteristic gene expression profile of lung-resident memory CD4+ T cells. This teaching reads on genes in the tissue resident memory CD4+ T cell are upregulated following administration to the subject (instant claim 7).
Rahimi et al. further teach “regulation and interaction with the ECM may play an important role in the development, maintenance, and function of [tissue resident memory T] cells in various tissues” (Pg. 10, column 2, ¶ 2, lines 24-26). This teaching gives motivation for generating the gene expression profile of lung-resident memory CD4+ T cells, as the upregulation of extracellular matrix organization proteins play an important role in the development, maintenance, and function of said cells—and thus would be beneficial in a therapeutic approach.
Regarding instant claims 19 and 26, Rahimi et al. further teach lung-resident memory CD4+ T cells have high CD49a expression and circulating memory CD4+ T cells have low CD49a expression (Fig. 5C, heatmap of genes shows Itga1 [CD49a] expression), indicating CD49a+CD4+ and CD49a-CD4+ cell populations. Rahimi et al. do not explicitly teach (i) the tissue resident memory CD49a+CD4+ T cells increase a proportion of CD49a+CD4+ to CD103+CD4+ cell phenotypes in a tissue of a subject (instant claim 19) nor (ii) IL17a expression in these two cell populations (instant claim 26). However, Collins et al. teach IL17a is downregulated in CD49a+CD4+ tissue resident memory T cells compared to CD49a-CD4+ ones (Fig. 4A, RNA sequence analysis of the two cell types; instant claim 26) and the reversal of “[CD49a+CD4+ to CD103+CD4+] skewing by adoptive transfer of CD49a+ CD4+ TRM” (Pg. 11, ¶ 2, line 9; instant claim 19) in a lung fibrosis mouse model. Therefore, (i) tissue resident memory CD49a+CD4+ T cells inherently increase a proportion of CD49a+CD4+ to CD103+CD4+ cell phenotypes in a tissue (i.e. the lung) of a subject (i.e. the mice) (instant claim 19) and (ii) IL17a is inherently downregulated in CD49a+CD4+ tissue resident memory T cells compared to CD49a-CD4+ ones (instant claim 26) as evidenced by Collins et al.
Tissue resident memory CD4+CD49a+ T cells located in the lung were known and used prior to the effective filing date of the application; these cells (i) exhibit a characteristic gene expression profile including extracellular matrix organization proteins such as Col1a1, Col1a2, and Dcn and (ii) inherently have downregulated expression of IL17a as compared to CD49a-CD4+ T cells and increase the CD49a+CD4+/CD103+CD4+ ratio in a tissue of a subject as evidenced by Collins et al. In addition, both US 443 and Rahimi et al. are in analogous arts (i.e. tissue resident memory T cells). Since Rahimi et al. teach the upregulation of extracellular matrix organization proteins play an important role in the development, maintenance, and function of lung-resident memory CD4+CD49a+ T cells, there is motivation for generating the gene expression profile of lung-resident memory CD4+CD49a+ T cells as taught by Rahimi et al. to enhance a therapeutic approach such as the method for treating fibrosis in a subject comprising administering a pharmaceutical composition comprising a T resident memory cell and a carrier suitable for inhalation or nebulization as taught in US ‘443. A person having ordinary skill in the art can administer tissue resident memory CD49a-CD4+ T cells (i.e. via inhalation or nebulization) to the target tissue (i.e. the lung) to achieve an enhanced therapeutic effect by upregulation ECM genes.
MPEP § 2141(III)(G) states a rationale that may support a conclusion of obviousness includes “[s]ome teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.” MPEP § 2143(I)(G) states this rationale should explain why “[a] person of ordinary skill in the art would have been motivated to combine the prior art to achieve the claimed invention and whether there would have been a reasonable expectation of success in doing so." DyStar Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick Co., 464 F.3d 1356, 1360, 80 USPQ2d 1641, 1645 (Fed. Cir. 2006).
The teaching, suggestion, or motivation in the prior art (i.e. the upregulation of extracellular matrix organization proteins play an important role in the development, maintenance, and function of lung resident memory CD49a-CD4+ T cells as taught in Rahimi et al.; said upregulation can be utilized to enhance therapeutic effects) would have led one of ordinary skill to modify the prior art reference (i.e. the method for treating fibrosis in a subject comprising administering a pharmaceutical composition comprising a T resident memory cell and a carrier suitable for inhalation or nebulization as taught in US ‘443 wherein the T resident memory cell is CD4+ and engrafted to the lung to generate the desired gene expression profile) to arrive at the claimed invention. There is a reasonable expectation of success as tissue resident memory CD4+CD49a+ T cells located in the lung were known and used prior to the effective filing date of the application; these cells (i) exhibit a characteristic gene expression profile including extracellular matrix organization proteins such as Col1a1, Col1a2, and Dcn and (ii) inherently have downregulated expression of IL17a as compared to CD49a-CD4+ T cells and increase the CD49a+CD4+/CD103+CD4+ ratio in a tissue of a subject as evidenced by Collins et al. In addition, both US 443 and Rahimi et al. are in analogous arts (i.e. tissue resident memory T cells).
It would have been obvious to a person having ordinary skill in the art prior to the effective filing date of the instant application to administer tissue resident memory CD49a-CD4+ T cells (i.e. via inhalation or nebulization) to the target tissue (i.e. the lung) to achieve an enhanced therapeutic effect by upregulation ECM genes, thereby modifying the method of treating fibrosis and pharmaceutical composition comprising tissue resident memory T cells of US ‘443 to arrive at the instant invention.
Claims 15 and 27 are rejected under 35 U.S.C. 103 as being unpatentable over US20210355443A1 (filed 2019-10-18, published 2021-11-18; hereinafter referred to as US ‘443) as evidenced by WebMD (Johnston, 2025, pgs. 1-4; WebMD, Saline (Sodium Chloride) for Nebulization - Uses, Side Effects, and More).
The ’443 and WebMD references are as discussed above and incorporated by reference herein.
As fully described in the 102 rejection section, US ‘443 teaches a method for treating fibrosis in a subject comprising administering a composition comprising a T resident memory cell (instant claim 1) and a pharmaceutical composition comprising said cell and a carrier suitable for inhalation or nebulization (instant claim 20), wherein a therapeutically effective dose of T resident memory cells is about 5×106 cells per kg body weight and the exact amount of immune cells is readily determined by one of skill in the art based on the age, weight, sex, and physiological condition of the subject.
US ‘443 does not explicitly teach the administered composition comprises about 5x103 – 5x106 cells (instant claims 15 and 27).
MPEP 2144.05(II)(A) states: "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
It is a common objective in the art to optimize result effective variables (i.e. amount of T resident memory cells), so as to achieve optimal effect and maximal benefit (i.e. tailor the dose to the age, weight, sex, and physiological condition of the subject). See In re Boesch, 617 F.2d 272, 276, 205 USPQ 215, 219 (CCPA 1980) “[D]iscovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art.”
Therefore, any optimization of the amount of T resident memory cells would be seen as routine optimization––and thus a person having ordinary skill in the art prior to the effective filing date of the instant application would immediately envisage the claimed amount of T resident memory cells to achieve it without undue experimentation in order to tailor the dose to the age, weight, sex, and physiological condition of the subject as taught by US ‘443.
Claims 18 are rejected under 35 U.S.C. 103 as being unpatentable over US20210355443A1 (filed 2019-10-18, published 2021-11-18; hereinafter referred to as US ‘443) as evidenced by WebMD (Johnston, 2025, pgs. 1-4; WebMD, Saline (Sodium Chloride) for Nebulization - Uses, Side Effects, and More) in view of Miltenyi Biotec (CD4 MicroBeads, 2020).
The ’443 and WebMD references are as discussed above and incorporated by reference herein.
As fully described in the 102 rejection section, US ‘443 teaches a method for treating fibrosis in a subject comprising administering a composition comprising a T resident memory cell (instant claim 1), wherein said cell is generated by contacting PBMCs with a CD3 antibody, a CD28 antibody, and IL-2 (instant claim 17).
US ‘443 does not teach isolation of the tissue resident memory T cell with a CD4 antibody and/or a CD49a antibody (instant claim 19).
Regarding instant claim 19, Miltenyi Biotec teaches CD4 Microbeads “conjugated to monoclonal anti-human CD4 antibodies” (Pg. 1, column 1, under “1. Description” heading, lines 2-3). Miltenyi Biotec further teaches “CD4 MicroBeads have been developed for the separation of human cells based on the expression of the CD4 antigen” (Pg. 1, column 1, last ¶, lines 1-2), specifically to isolate “CD4+ T cells from peripheral blood” (Pg. 1, column 2, under “1.3 Applications” heading, lines 1-2). This teaching reads on isolation of a T cell with a CD4 antibody (instant claim 19).
Miltenyi Biotec further teaches CD4 is important for “recognition of MHC class II/peptide complexes” (Pg. 1, column 1, last ¶, line 5), indicating CD4+ T cells would be beneficial for an enhanced immune response.
US ‘443 and Miltenyi Biotec are analogous arts (i.e. T cells from peripheral blood). It would have been obvious to a person having ordinary skill in the art prior to the effective filing date of the application to utilize a CD4 antibody to isolate a tissue resident memory T cell because (i) US ‘443 teaches generating tissue resident memory T cells from PBMCs and their subsequent use in a method of treating fibrosis and (ii) Miltenyi Biotech teaches microbeads conjugated to anti-CD4 antibodies can be used to select for CD4-expressing T cells from peripheral blood (applicable to PBMCs).
The prior art includes each element prior to the effective filing date of the application, the only difference between the claimed invention and the prior art being the lack of actual combination of the elements in a single prior art reference. A person having ordinary skill in the art prior to the effective filing date of the application would be motivated to utilize a CD4 antibody to isolate a tissue resident memory T cell as CD4 is important for recognition of MHC class II/peptide complexes and therefore would be beneficial for an enhanced immune response.
MPEP 2143(I)(A) states, “The rationale to support a conclusion that the claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results to one of ordinary skill in the art. KSR, 550 U.S. at 416, 82 USPQ2d at 1395; B/E Aerospace, Inc. v. C&D Zodiac, Inc., 962 F.3d 1373, 1379, 2020 USPQ2d 10706 (Fed. Cir. 2020); Sakraida v. AG Pro, Inc., 425 U.S. 273, 282, 189 USPQ 449, 453 (1976); Anderson’s-Black Rock, Inc. v. Pavement Salvage Co., 396 U.S. 57, 62-63, 163 USPQ 673, 675 (1969); Great Atl. & P. Tea Co. v. Supermarket Equip. Corp., 340 U.S. 147, 152, 87 USPQ 303, 306 (1950).”
Both US ‘443 and Miltenyi Biotec teach methods comprising T cells from peripheral blood. It is routine in the art to isolate cells with magnetic beads such as CD4 microbeads manufactured by Miltenyi Biotec, indicating isolating with said microbeads would be successful.. A person having ordinary skill in the art would recognize the results of the combination were predictable (i.e. the CD4 microbeads would reliably isolate CD4-expressing T cells, applicable to tissue resident memory T cells) and have a reasonable expectation of success.
Conclusion
Claims 1-27 are pending. Claims 23 and 26 are objected to. Claims 1-27 are rejected. No claims are allowed.
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/J.M.P./Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642
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