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 1-16 are pending and under examination in the present Official Action.
Priority
The present application is a continuation in part of International Application No. PCT/IB2022/054328, filed 10 May, 2022, which claims priority to United States Provisional Application No. 63186331, filed 10 May, 2021. Acknowledgment is made of applicant’s claim for priority.
The earliest possible priority for the instant application is 10 May, 2021.
Drawings
The drawings filed 09 November, 2023 and the replacement drawing for FIG. 2 filed 30 January, 2024 are accepted by the Examiner.
Claim Objections
Claims 1, 2, 5, 7 are objected to because of the following informalities: The use of the word “respective” in each context where it is used is unnecessarily verbose. The claim limitations which recite “respective” would have the same meaning without reciting “respective” and an amendment to remove “respective” would improve the conciseness of the claims. 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.
Claims 1-16 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.
Claims 1-2 each recite the limitation "the one or more single plasma cells that secrete the antibody fragment" in the eighteenth line of each claim. There is insufficient antecedent basis for this limitation in the claim. Claims 1 and 2 are independent claims and so they must set forth antecedent basis for limitations within themselves. Nowhere in either claim 1 nor claim 2 is there a recitation of “one or more single plasma cells that secrete the antibody fragment”. Therefore, there is no antecedent basis for referring to "the one or more single plasma cells that secrete the antibody fragment". Even further, it is unclear how a single plasma cell secretes an “antibody fragment” since plasma cells are known in the art to secrete full-length antibodies. Claims 3-16 are further rejected for their dependency on a rejected base claim.
The term “predetermined” in claim 2 is a relative term which renders the claim indefinite. The term “predetermined” 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. There is no definition for the term “predetermined” in the specification and the claims do not set forth what the scope of “predetermined” is. Therefore, claim 2 is rejected for being indefinite. Claims 3-16 are further rejected for their dependency on a rejected base claim.
Claim 9 is indefinite for reciting a use without reciting any positive steps delineating the use. Claim 9 recites “using a screening assay” in the last line of the claim. Claim 9 does not provide any positively recited steps delineating what “using a screening assay” entails. Thus, a skilled artisan would not be reasonably apprised of the scope of the protection sought by claim 9.
Claims 14-16 each recite the limitation "the one or more nucleic acid sequences" in the first line of each respective claim. There is insufficient antecedent basis for this limitation in the claim. Neither claim 8, nor claim 7, nor claim 2 from which each of claims 14-16 depend recite one or more nucleic acid sequences. Therefore, there is insufficient antecedent basis for these limitations.
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 1-16 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 written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Notably the issue of a lack of written description may arise even for an original claim when an aspect of the claimed invention has not been described with sufficient particularity such that one skilled in the art would recognize that the applicant has possession of the claimed invention. This issue may also arise when the claimed invention, as a whole, is not adequately described and more particularly where the claims require an essential or critical feature which is not adequately described in the specification and which is not conventional in the art or known to one of ordinary skill in the art. Furthermore, this issue may arise where an invention is described solely in terms of a method of its making coupled with its function and there is no described or art-recognized correlation or relationship between the structure of the invention and its function. Finally, a lack of adequate written description issue may also arise when the knowledge and level of skill in the art would not permit one skilled in the art to immediately envisage the product claimed from the disclosed process.
In this case, the claims are drawn to a method for producing an antibody fragment comprising a step of “detecting the one or more single plasma cells that secrete the antibody fragment”. Both independent claim 1 and independent claim 2 recite this step. Thus, the claims require a plasma cell that secretes the antibody fragment which itself is the product of the method (“the” indicating that the antibody fragment in the preamble is the same as the one secreted from the plasma cells). The scope of the claims is broad in the sense that “antibody fragment” is itself a broad genus of molecules encompassing “one or more of Fab, Fab’, F(ab’)2, Fc, Fv, scFv fragments, heavy chain, hinge region, light chain, antigen binding site, and single chain antibodies” (Specification, [0024]). Further, claim 2 is drawn to a method for producing an antibody fragment which concludes with “detecting one or more single plasma cells that secrete the antibody fragment”. In addition to the breadth of this recitation already discussed supra, claim 2 broadly encompasses producing an antibody fragment by detecting the antibody fragment without requiring any actual steps for production of the antibody fragment.
The specification provides a working example in which a human is immunized against tetanus toxoid ([0058]), that human’s PBMCs are isolated and plasma cells FACS-sorted to select single plasma cells ([0059]-[0060]), those single plasma cells are cultured ([0061]-[0062]), and then the cultured single plasma cells are screened to “Detect Single Plasma Cells Secreting Anti-tetanus IgG antibodies” (“Example 4”). The working examples specifically teach that the antibodies secreted from the plasma cells are anti-tetanus IgG antibodies ([0064]). The working example goes on to teach isolation of total RNA from the plasma cells, followed by cDNA generation and PCR using the cDNA to generate VH and VL chains ([0066]-[0067]). The working examples then teach the assembly of the VH and VL chains using overlap PCR into an scFv ([0070]). The working examples also teach the expression of the scFv in E. coli cells ([0073]). Thus, the working examples describe two distinct antibodies, one which is the complete IgG produced by the plasma cells, and one which is an scFv antibody fragment produced through overlap PCR of the nucleic acids encoding VH and VL chains. The plasma cells in the working examples themselves do not secrete the antibody fragment that is the product of the method, nor do they secrete an antibody fragment at all but rather a full-length IgG antibody. In addition, to the extent the working examples teach production of an antibody fragment, it is the production of an scFv via RNA extraction, cDNA synthesis, overlap PCR, and expression in a host cell.
Indeed, the skilled artisan in the field of plasma cell culture knows that plasma cells secrete full-length antibodies (Tellier et al., Eur J Immunol. (2019) 49(1):30-37. doi: 10.1002/eji.201847517. Epub 2018 Oct 15. PMID: 30273443.). Tellier teaches that plasma cells, whether short-lived or long-lived, secrete full-length antibodies which can be either IgM, IgG, or IgA isotype (Tellier, Figure 1). Thus, a plasma cell secreting an antibody fragment would deviate from the art at the time of filing and present a new field of endeavor, requiring adequate description of such an accomplishment to be able to demonstrate possession to the skilled artisan.
In view of the breadth of the claims encompassing plasma cells secreting antibody fragments and a method of production merely comprising detection, the limitation of the working examples to plasma cells secreting full-length IgG antibodies, and the relative lack of guidance in the art at the time of filing for plasma cells secreting anything but full-length antibodies, the claimed invention has not been described with sufficient particularity such that one skilled in the art would recognize that the applicant has possession of the claimed invention.
Additional Comments
The closest prior art to the instant invention is Bazzaz, et al. Journal of Isfahan Medical School 32.282 (2014): 534-543. Bazzaz et al. teaches a method for single primary plasma cell culture to make human monoclonal antibodies (mAb) (Bazzaz, English Language Abstract, end of document). The method of Bazzaz includes the use of bone marrow stromal cells (BMSCs) as feeder cells and the extraction of RNA with RT-PCR to detect antibody sequences (Bazzaz, English Language Abstract, end of document).
Another relevant prior art publication is Tiller, et al. Journal of immunological methods 329.1-2 (2008): 112-124. Tiller teaches a similar method to Bazzaz but Tiller goes further to teach cloning of the mAb sequence and expression in a host cell (Tiller, “Expression vector cloning” and “Recombinant antibody production”).
Finally, Salai et al. (Salai, et al. The Journal of Bone & Joint Surgery British Volume 83.6 (2001): 912-915.) teaches the inhibitory effects of colchicine on human stromal bone marrow cells (HSBMCs) (Salai, page 912, third paragraph; Title). Salai teaches that colchicine inhibits proliferation of BMSCs at concentrations from 10-30 ng/mL and not at a concentration up to 3 ng/mL (Salai, pages 913-914, last partial and first partial paragraphs respectively). Salai goes on to teach that at concentrations up to 3 ng/mL, colchicine reduces mineralization of the cells (Salai, page 914, first full paragraph).
None of the cited prior art references alone or in combination provide substantial evidence to teach, suggest, or provide a person having ordinary skill in the art a motivation to practice the invention as currently claimed because neither Bazzaz, nor Tiller, suggest to reduce mineralization of BMSCs while maintaining their proliferative capacity when BMSCs are used as feeder cells.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BRENDAN THOMAS TINSLEY whose telephone number is (703)756-5906. The examiner can normally be reached Mon-Fri 8:00-5:00.
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/BRENDAN THOMAS TINSLEY/Examiner, Art Unit 1634
/MARIA MARVICH/Primary Examiner, Art Unit 1634