Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Claim Status
1. Currently, claims 1-14 and pending and under consideration.
Priority
2. The instant application has a priority date of June 24, 2020. This application is a
371 of International Application No. PCT/IB2021/055413, filed on June 18, 2021, which published in the English language on December 30, 2021, under International Publication No. WO 2021/260512 A1, which claims priority to U.S. Provisional Application No. 62/705,383, filed on June 24, 2020.
Information Disclosure Statement
3. The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609 A(1) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the Examiner on form PTO-892 or Applicant on PTO-1449 cited the references they have not been considered.
4. The Information disclosure Statement (IDS) filed on 3/16/23 has been considered as to the merits before the First Action.
Specification
5. The use of the term TWEEN (i.e. see page 42 line 18 and page 60 lines 28 and 34), NANOPORE on page 49, and TRITON (i.e. page 44 line 13), which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
6. The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01. See page 42 line 28.
Abstract
7. This application does not contain an abstract of the disclosure as required by 37 CFR 1.72(b). An abstract on a separate sheet is required.
Claim Objections
8. Claims 4, 12, 13 and 14 are objected to because of the following informalities: The claims utilizes several acronyms “MHC, CD69, CTLA4, LAG3, CD45, CD138, CD45R, etc.” without first defining what it represents in the independent claim. While the claims can reference acronyms, the material presented by the acronym must be clearly set forth at the first use of the acronym. Although the term may have art recognized meaning, it is necessary to define the acronym to clearly set forth Applicant’s intent. For example, MHC is defined as “major histocompatibility complex” on page 17 line 12 and page 15 lines 20-21. Applicant is cautioned not to introduce new matter into the claims when defining the terms. Appropriate correction is required
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
9. Claims 1-14 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 pre-AIA the applicant regards as the invention.
A. In claim 1, the term "represented" is indefinite because it is unclear whether this requires, (a) at least one physical copy of each ligand and receptor to be present in the set, (b) or at least one physical copy of each ligand set and each receptor set for analysis. The claims do not provide a standard for ascertaining which of these interpretations is intended, and one of ordinary skill in the art would be reasonably apprised of the scope of the invention. While claim 1 appears to be directed to a method of identifying a cognate ligand species wherein a set of ligand species and receptors species are contacted in a microreactor to generate an enhanced signal for identification. The method does not clarify if the language indicating that the ‘species is represented at least one time’ is directed to the set or a single ligand/receptor. This makes the claim indefinite as the claims fail to specify the limitation, leaving one of ordinary skill in the art unable to determine the metes and bounds of the claimed invention. Appropriate correction is required.
B. The term “enhanced signal” in claim 1 is a relative term which renders the claim indefinite. The term “enhanced signal” is not defined by the claim, 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 specification merely teaches that an enhanced signal is produced as a result of T cell binding/activation, but does not teach how said signal will be determined (measured in units) or the comparison that is indicative of enhanced signaling (is an initial signal required for comparison to determine enhancement?). This makes that claims ambiguous. It is suggested that the actual detection limits of the signal are added to the claim in order to obviate the rejection. Appropriate correction is required.
C. Claim 4 recites the limitation "antigen-presenting cell" in claim 3. There is insufficient antecedent basis for this limitation in the claim. It is suggested that consistent claim language is utilized throughout the claims for clarity. Appropriate correction is required.
D. Regarding Claim 9, it is unclear how long the contact or micro-reaction step will last. The use of “about” and “at least about” with hours is unclear. Will the reaction occur from 0.001 hours to 8 hours. If not, what other times are contemplated by the claim? For example, will 12 hours encompass the claim language? It is suggested that the terms “about” and at least about” are removed from the claim language in order to obviate the rejection. Please clarify the intended reaction time.
Claim Rejections - 35 USC § 102
10. 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.
11. Claim(s) 1-11 is/are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Berka et al. (WO2017/013170) Published 1/26/2017.
Claim 1 is drawn to a method of identifying a cognate pair of a ligand species and a receptor species, the method comprising: a. providing a set of ligand species, wherein each ligand species is represented at least one time; b. providing a set of receptor species, wherein each receptor species is represented at least one time; c. contacting the set of ligand species with the set of receptor species in a microreactor, wherein upon selective binding of a ligand species with a receptor species an enhanced signal is produced; d. detecting a cognate pair of ligand species and receptor species by the production of the signal; and e. identifying the cognate pair of ligand species and receptor species.
In the context of the invention, the term "cognate pair" of ligands and receptors refers to the pair of a ligand species and the receptor species to which it selectively binds. By "selectively binding" is meant herein that one member of the pair recognizes and binds to the other member of the pair with greater affinity than to a member of another pair. See specification page 13 lines 9-12
Berka et al. teach a method for identifying a receptor species or T cell receptor (TCR) and a ligand species or epitope peptide pair that specifically binds the T cell of interest (Abstract; Figure 1; Paragraph 26, lines 13-15). T cell receptors-antigens and B cell receptors-antigens are taught by the disclosure at least on page 1 lines 10-12. The method of Berka et al. comprising: providing different mixture partitions or subsets of receptors including a population of T cells, the T cells comprising different TCRs having a TCR heavy chain encoded by a TCR heavy chain nucleic acid and a TCR light chain encoded by a TCR light chain nucleic acid or a set of ligand species with at least one represented species (Paragraph 27: lines 17-21; Paragraph 29, lines 10-20).
Berka also teaches identifying a portion of the T cells, comprising TCRs that specifically bind to a portion of the positive ligand sub-sets or epitope peptides present in the mixture (Figures 2-3; Paragraph 30, lines 22-25) containing partition-specific barcodes (Paragraph 30, lines 25-26) for encoding purposes (Paragraph 30, lines 26-27) or a set of receptor species with at least one represented species. Further, Berka teaches that in the mixture partitions, through generating these barcoded nucleic acids by attaching the partition-specific barcodes to the specified TCRs (i.e., heavy chain, light chain) and epitope nucleic acids (Paragraph 35, lines 19-22), followed by pooling of these mixtures (Figure 2; Paragraph 35, lines 22-23), for sequencing (Figure 3; Paragraph 35: lines 23-30) to establish a subset of these positive microreactors or TCRs that specifically contain the same specified regions that co-segregate or co-compartmentalize in a larger number of partitions by chance or determination of probability, and classifying these as encoding a TCR that binds to the epitope peptide or ligand (Paragraph 38 lines 24-33; Paragraph 58, lines 1-20).
Berka teaches that if the probability is greater than a predetermined threshold, the co-segregated epitope or positive ligand with the TCR at higher than chance frequency would be the most frequent epitope paired with that TCR (Paragraph 37, lines 6-15; Paragraph 38, lines 30-33; Paragraph 59, lines 17-25).
Berka teaches sequencing and identifying the antigen receptor complexes via signal detection with cell surface markers (CD30, CD38, CD45RA, CD45R, CD294, CCR5, CXCR4 and TLR2-5) or with an MHC molecule.
Berka teaches that the methods can be performed on a population of T cells for multiplex or highly parallel analysis of the population of TCR specificities, in order to probe a population of T-cells to identify one or more TCRs that specifically bind to an epitope peptide (Paragraph 26, lines 1-5).
Regarding claim 2, Berka teaches the method further comprises, determining a partition segregation pattern for specified TCRs (i.e., heavy chain, light chain) and epitope peptides or ligands by identifying these receptor sub-sets through comparison of barcode regions (Paragraph 13, lines 16-21; Paragraph 37, lines 18-25) and classifying receptor sub-sets and ligands sub-sets through co-segregation or co-compartmentalizing in a larger number of partitions than expected by chance or the probability as encoding a receptor and ligand species that specifically bind to each other to form classes of positive or negative microrcactors or heavy and light chain barcoded regions (Paragraph 38, lines 24-33; Paragraph 59, lines 1-5). Further, Berka teaches that, if the probability is greater than a predetermined threshold, the positive microreactor, containing the same species, with the TCR at higher than chance frequency would be the most frequent epitope or ligand paired with that TCR (Paragraph 38, lines 30-33; Paragraph 58, lines 1-10).
Regarding claim 3, Berka teaches epitope nucleic acids immobilized on solid supports such that each solid support has a clonal population of immobilized epitope nucleic acids or ligand species (Figure 3; Paragraph 33, lines 11-14).
Regarding claim 4, Berka teaches that epitope peptides or ligand species are displayed on individualized particles (i.e., MHC (major histocompatibility complex class I) class I proteins with heavy chain), where each microreactor or paired ligand and receptor species contain 1 or a range of 2-8 individualized particles (Figures 2-3; Paragraph 34, lines 5-7; Paragraph 41, lines 26-31).
Berka teaches the MHC-displayed epitope peptides or ligand species are provided by; partitioning a library of epitope nucleic acids or ligands encoding the epitope- fused to beta-microglobulin and a binding peptide responsible for binding a surface-immobilized binding partner, where each surface has a clonal population of the nucleic acids of interest (Paragraph 35, lines 3-9; Paragraph 62, lines 28-31). Berka further teaches that in-vitro transcribing and translating the nucleic acids to generate surface-immobilized epitope peptides fused to beta-microglobulin and the binding peptide bound to the binding partner, each surface having a clonal population of the peptides and encoding nucleic acids (Paragraph 35, lines 9-18; Paragraph 63, lines 5-15; Paragraph 64, lines 15-40), followed by refolding the epitope proteins or ligands with specialized particles (i.e., MHC class I) (Paragraph 35, lines 18-19; Paragraph 63, lines 5-15).
Regarding claims 5 and 9, Berka teaches a method where mixture partitions comprise classifying barcoded or paired TCR sub-sets and ligand sub-sets or microreactors and have the same barcode as encoding the receptor and ligand that specifically bind (Paragraph 7, lines 3-14; Paragraph 40, lines 19-27).
Further, Berka teaches that probability or chance of classification is determined by a function of the diversity of ligand species and the average number of specialized microreactors for binding (Paragraph 2, lines 15-25; Paragraph 40, lines 23-27).
Regarding claim 6, Berka teaches a method in which the addition of reverse transcriptase, cell lysis or purification buffer, deoxynucleotide triphosphates (dNTPs), and many different barcoded primers specific for a nucleic acid sequence encoding the ligand and of barcoded primers specific for a nucleic acid sequence encoding the receptor are added for purification and further analysis or immobilization purposes to the mixture partitions or subsets (Figure 3; Paragraph 32, lines 13-29). Berka teaches that the barcoded primers specific for the ligand-encoding or epitope nucleic acid sequence comprise primer sequences specific to the ligand-encoding nucleic acid sequence and a barcode sequence or barcode set of sequences (Paragraph 31, lines 1-15; Paragraph 35, lines 18-26). Berka teaches that the barcoded primer specific to the receptor-encoding nucleic acid sequence comprise a primer sequence specific for the TCR or receptor-binding nucleic acid sequence and barcode sequence or barcode set of sequences (Paragraph 37, lines 15-22). Berka further teaches that the barcode sequence or set of sequences contained a microreactor or pairing of ligand or epitope peptide and receptor (i.e., TCR) species that is distinguishable from others, due to a shared sequence or set of sequences (Paragraph 40, lines 20-25).
Regarding claim 7, Berka teaches a method where the receptor set of interest are TCRs and the set of ligands is a set of T cell antigens (Figure 1, Abstract).
Regarding claims 8, 10, and 11, Berka teaches a method where soluble TCR can then be assayed for binding to an epitope peptide or ligand species to determine T cell activation/recognition or lack thereof (i.e., positive or negative) (Figure 1; Paragraph 70, lines 30-33).
Berka teaches each and every limitation of claims 1-11, and therefore Berka anticipates claims 1-11.
Claim Rejections - 35 USC § 103
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.
12. Claim(s) 12, 13, and 14 is/are rejected under 35 U.S.C. 103 as being unpatentable over Berka et al. (WO2017/013170) Published 1/26/2017, in view of Hause et al. (WO 2019/051335) submitted on IDS dated 3/1/23 and Sava, Florentia et al. "Expression of lymphocyte activation markers of preterm neonates is associated with perinatal complications," BMC Immunology, volume 17, issue 1 (December 1, 2016), 7 pages, submitted on IDS dated 3/16/23.
Please see Berka et al. as set forth above. Berka et al. differ from the instant invention in not specifically teaching the measurement of markers and/or antibody markers with a link to T cell activation.
However, Hause et al. teach
Hause et al. relates to a number of cell surface makers, cytokines and other factors involved in function of immune cells, like T cells. Markers associated with for example function, activation state and maturity include CD27, HLA-DR, IFN- gamma, PD-1, TIM-3, CD45RA, CD45RO, see D4 par. [0409]-[0411]. Hause et al. teach that T cell markers may be helpful in therapeutic procedures. See abstract.
While Sava et al. refers to early, late and very late T cell activation markers, like CD25, CD69, CD62L, HLA-DR and VLA-1 and to specific antibodies thereto, see page 2, left-column; page 3. Sava et al. disclose that alterations affecting the expression of T lymphocyte activation markers may play a role in the development of perinatal complications. Conclusion.
Thus absent evidence to the contrary, the detection of specific early or late T cell activation markers using markers or antibodies is obvious. Early and late T cell activation markers and antibodies thereto are known as demonstrated by the prior art references to Hause et al. and Sava et al.
Therefore, it would have been obvious to measure known T cell activation markers and/or antibodies as taught by Hause et al. and Sava et al. in the T cell activation measurements of Berka et al. in order to monitor the T cell state (early, late, etc.) as a means to formulate therapeutics and monitor disease/disorders.
13. For reasons aforementioned, no claims are allowed.
14. Any inquiry concerning this communication or earlier communications from the examiner should be directed to Lisa Cook whose telephone number is 571-272-0816. The examiner works a flexible schedule but can normally be reached on Monday-Friday from 9am to 5pm.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Samira Jean-Louis, can be reached at telephone number 571-270-3505. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Lisa V. Cook
Patent Examiner
Art Unit 1642
Remsen
571-272-0816
3/7/26
/LISA V COOK/Primary Examiner, Art Unit 1642