DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 1-6, 10-11, 13-14, 16-20, and 22-23, of record 7/9/2026, are pending and subject to prosecution. Claims 1, 5-6, 10, 16, and 22-23 are amended. Claims 7, 9, and 15 are cancelled.
Status of Prior Rejections/Response to Arguments
RE: Objection to claims 1, 15, and 22-23:
The cancellation of claim 15 renders the objection thereto moot.
The amendment to claims 1 and 22-23 is effective to obviate the objection. The objection is withdrawn.
RE: Rejection of claims 1-7, 9-11, 13-20, and 22-23 under 35 U.S.C. 112(b):
The cancellation of claims 7, 9, and 15 renders the rejection thereto moot.
The amendment to claims 1, 5-6, 10, and 22 is effective to obviate the rejection over claims 1-6, 10-11, 13-14, 18-20, and 23. The rejection over those claims is withdrawn.
The applicant has traversed the rejection over the use of AF594 and AF488 in claims 16-17 and 22, asserting that these trademarked Alexa Fluor fluorophores have well-defined structures and properties and would be understood by one of ordinary skill (Applicant Remarks, page 6).
This argument is not found persuasive. If a trademark or trade name is used in a claim as a limitation to identify or describe a particular product, the claim does not comply with the requirements of 35 U.S.C. 112(b). See MPEP 2173.05(u). Here, the trademarks are used to identify a sulfonated fluorescein and a sulfonated rhodamine derivative for which there are structurally identical equivalents commercially available; thus, “AF” or “Alexa Fluor” identifies the source of the product rather than the product itself, which further constitutes an improper use of the trademark or trade name. See MPEP 2173.05(u).
The rejection over claims 16-17 and 22 is therefore maintained.
RE: Rejection of claims 1-7, 9, 11, 14-15, 18-19, and 23 under 35 U.S.C. 103 over Park et al. (WO 2018076024 A2) in view of Roschke et al. (US 20140065142 A1):
RE: Rejection of claims 1-7, 9-11, 14-15, 18-20, and 23 under 35 U.S.C. 103 over Park et al. (WO 2018076024 A2) in view of Roschke et al. (US 20140065142 A1), further in view of Le et al. (Biotechnology Journal, 2020):
The cancellation of claims 7, 9, and 15 renders the rejections thereto moot.
The amendment to independent claims 1 and 23 is effective to obviate the rejections. The rejections are withdrawn.
RE: Rejection of claims 1-7, 9-11, 14-15, 18-19, and 23 under 35 U.S.C. 103 over Park et al. (WO 2018076024 A2) in view of Roschke et al. (US 20140065142 A1), further in view of Buie et al. (Annals of Pharmacotherapy, 2015):
RE: Rejection of claims 1-7, 9-11, 13-19, and 22-23 under 35 U.S.C. 103 over Park et al. (WO 2018076024 A2) in view of Roschke et al. (US 20140065142 A1), further in view of Buie et al. (Annals of Pharmacotherapy, 2015), further in view of Backer et al. (Methods in Molecular Biology - Peptide-based Drug Design, 2008) and Kumar et al. (Current Science, 2012):
The cancellation of claims 7, 9, and 15 renders the rejection thereto moot.
The applicant asserts that the amended claims address a specific technical problem relating to the screening of BiTE-secreting clones on a nanofluidic chip, that Park et al. teach screening methods directed to B cells that naturally produce antibodies rather than engineered cells expressing BiTEs, and that Roschke et al. teach the claimed CD3-binding peptide in a fundamentally different analytical approach versus the instant invention (Applicant Remarks, page 7-9).
The applicant’ arguments have been fully considered but are not found persuasive. As an initial matter, the motivation to modify a reference need not be the same as the applicant’s (i.e., the screening of cell clones for levels of poorly-expressed BiTEs). See MPEP 2144(IV). Park et al. teach that the antibody-producing cells assayed by their methods can be engineered cells, including hybridomas and transfected and/or transformed cells (See ¶0044), which would encompass BiTE-expressing cells. Additionally, the focus of Roschke et al. on antibody complexes does not render their disclosure of QDGNEEMGG as a peptide for binding CD3-specific multivalent antibodies any less relevant or suitable for combination with the other cited prior art teachings.
The rejection is therefore maintained in modified form to address amended limitations.
New/Maintained Rejections
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 16-17 and 22 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 16-17 and 22 contain the trademarks/trade names AF or AlexaFluor. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe engineered fluorophores and, accordingly, the identification/description is indefinite.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-6, 10-11, 14, 18-19, and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Park et al. (WO 2018076024 A2), of record, in view of Roschke et al. (US 20140065142 A1), of record, and Buie et al. (Annals of Pharmacotherapy, 2015), of record.
Regarding claims 1-2, 5, 7, 10-11, 14, and 18: Park et al. teach methods for screening antibody-producing (which reads on “secretes a biomolecule” and “polypeptide”) cells within microfluidic or nanofluidic environments (See Abstract and ¶0037-0038, 0054, and 0072). Park et al. teach a microfluidic or nanofluidic device or chip comprising one or more fluidically interconnected circuit elements (See ¶0036-0038). Sequestration pens facilitate the loading of single cells and growth of clonal colonies of antibody-producing cells (See ¶0093). The cells used in the assay can be eukaryotic, plant, bacterial, fungal, or mammalian; can be cells from a cell line; and can be transfected (See ¶0044). The cells are manipulated into sequestration pens and screened for expression of antibodies that specifically bind to an antigen of interest, which can be a protein (See ¶0003, 00101, and 0226). The antigen of interest is introduced into the device such that it is proximal to the antibody-producing cell (which reads on “administering a composition… to said nanofluidic chip under conditions… to contact said biomolecule”), which can be one of a population of cells (See ¶0005 and 0230). The antigen of interest can be labeled (“which reads on “peptide-conjugate comprising at least one modification”) with a fluorophore (See ¶0005). In example 1, Park et al. teach that a group of splenocytes associated with antibody binding could be separated and moved into new sequestration pens as single cells and reassayed (See ¶00282-00288). Sequestered single cells can be exposed to activation/culture medium for several days before being assayed for antibody secretion and antigen specificity, as taught in example 2 (See ¶00298-00299). The cells can be expanded within the device during culturing (See ¶00168 and 00237). The assay can be multiplexed for additional antigens and repeated (See ¶00306 and 00308), which would yield single cells secreting antibodies against one or more antigens of interest.
Park et al. therefore render obvious the isolation and clonal expansion of single antibody-producing cells from a population, assaying for antibody secretion and specificity through exposure to an antigen, and isolating single cells that produce a desired antibody or antibodies. However, Park et al. do not teach the antibody as anti-CD3 BiTE or the antibody ligand as a CD3 peptide.
Buie et al. review the anti-CD3/anti-CD19 BiTE blinatumomab, which can be produced in CHO cells (See page 1058, col. 2, ¶2).
Roschke et al. teach multivalent, multispecific antibodies comprising molecular recognition domains (See Abstract). The antibodies can bind to a target on a cell or tissue of interest and to a target on an effector cell, such as CD3 epsilon (See ¶0019-0020). The antibodies can bind a CD3 epsilon polypeptide having the sequence QDGNEEMGG (which reads on “a CD3 peptide” and “comprises… 9… amino acids”) (See ¶0415, SEQ ID NO 31). Host cells can be transformed with viruses or plasmids (which read on “expression construct”) for expressing the antibodies (See ¶0572 and 0583). The host cells can be CHO, BHK, NS0, SP2/0, PER.C6, or 293 cells (See 0355 and 0572). Antibody binding and activity can be determined by using or modifying assays known in the art (See ¶0245).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the methods taught by Park et al. to comprise expression of a CD3/CD19 BiTE, such as is taught by Buie et al., by the screened cells Combining prior art elements in order to yield predictable results is considered to be prima facie obvious. See MPEP 2143(I)(A). Each element would retain its properties and functions in the combination, and one of ordinary skill would have readily recognized that the results of the combination would be predictable.
It also would have been obvious to one of ordinary skill to modify the methods taught by Park et al. to comprise the CD3 epsilon peptide sequence taught by Roschke et al. as the antigen of interest. One would have been motivated to make this modification because Roschke et al. teach it as an epitope for multivalent, multispecific antibodies targeting human CD3 (See 0415), and such a modification could be readily made.
Regarding claim 3: Following the discussion of claims --1-2, 5, 10-11, 14, and 18, Park et al. teach that when the antibody-producing cells are B cells, they can be contacted within the device with a stimulating agent such as T cells or a CD40L-expressing cell line (which reads on “the population of cells is a mixture of two or more cell lines”) (See ¶00236).
Regarding claim 4: Following the discussion of claims 1-2, 5-6, 10-11, 14, and 18, Park et al. teach that the antibodies can be analyzed by ELISA (which reads on “quantifying the amount of said biomolecule secreted”) (See ¶00301).
Regarding claim 19: Following the discussion of claims 1-2, 5-6, 10-11, 14, and 18, Park et al. teach that the antibody-expressing cell can be cultured within the device for a period of one to ten days and teach a four-day culture/activation period using B cells in example 2 (See ¶00237 and 00298). The screening process itself for isolating cells secreting antibodies specific to an antigen is performed in less than a day (See ¶00318), which suggests that isolation of a single cell, clonal expansion, assaying for antigen-specific antibody secretion, and single cell isolation could be readily completed in 14 days or less.
Regarding claim 23: Following the discussion of claims --1-2, 5-6, 10-11, 14, and 18, Park et al., modified by Roschke et al., render obvious a method for screening antibody-producing cells but do not teach culturing isolated single cells secreting an anti-CD3 antibody after transfer to a vessel.
However, Roschke et al. teach that stable transgene expression is more amenable than transient expression to large-scale production of the antibody (See ¶0583), which would necessarily require transfer of the isolated cells to another, larger vessel for culturing and antibody secretion.
Claims 1-6, 10-11, 13-14, 16-19, and 22-23 are rejected under 35 U.S.C. 103 as being unpatentable over Park et al. (WO 2018076024 A2), of record, in view of Roschke et al. (US 20140065142 A1), of record, further in view of Buie et al. (Annals of Pharmacotherapy, 2015), of record, further in view of Backer et al. (Methods in Molecular Biology - Peptide-based Drug Design, 2008), of record, and Kumar et al. (Current Science, 2012), of record.
The teachings of Park et al., Roschke et al., and Buie et al. are set forth in the rejections above and are incorporated herein in their entirety.
Regarding claims 13, 16-17, and 22: Following the discussion of claims 1-6, 10-11, 14, 18-19, and 23, Park et al. teach that the antigen can be labeled with an Alexa Fluor dye but do not teach the dye as AF594 or teach a pyroglutamate residue.
Backer et al. teach methods for labeling proteins or peptides via cysteine residues (See Summary). A terminal cysteine can be inserted for site-specific modification with imaging agents (See page 276, ¶1). In an example, VEGF is labeled with Alexa Fluor 594 maleimide (See page 283, full ¶3 and fig. 4A).
Kumar et al. review pyroglutamic acid (See Abstract). Pyroglutamate is a common N-terminal modification to proteins and biologically active peptides resulting from the cyclization of glutamate or glutamine and may serve to protect against degradation (See page 289, col. 2, ¶2; page 290, col. 1, ¶1; and page 291, col. 2, ¶1-2).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the antibody-binding CD3 peptide taught by Roschke et al. to add a C-terminal cysteine for maleimide linkage of an AF594 label. One would have been motivated to make this modification because Backer et al. teach the addition of a terminal cysteine as one strategy for site-specific labeling of peptides and demonstrate that maleimide-linked AF594 can be successfully used for labeling without altering protein function (See page 276, ¶1; page 283, full ¶3; and fig. 4A).
It also would have been obvious to replace the N-terminal glutamine of the CD3 peptide with pyroglutamate. One would have been motivated to make this modification because Kumar et al. teach that it may protect peptides against degradation (See page 290, col. 1, ¶1; and page 291, col. 2, ¶1-2). There would be a reasonable expectation of success in doing so because Kumar et al. teach that this modification commonly occurs naturally in peptides and proteins (See page 289, col. 2, ¶2 and page 290, col. 1, ¶1). Carrying out these modifications would yield a peptide having the sequence of instant SEQ ID NO 1, pyroglutamate-DGNEEMGGC, with AF594 conjugated to the cysteine residue with a maleimide linkage.
Claims 1-6, 10-11, 14, 18-20, and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Park et al. (WO 2018076024 A2), of record, in view of Roschke et al. (US 20140065142 A1), of record, and Buie et al. (Annals of Pharmacotherapy, 2015), of record, further in view of Le et al. (Biotechnology Journal, 2020), of record.
The teachings of Park et al., Roschke et al., and Buie et al. are set forth in the rejections above and are incorporated herein in their entirety.
Regarding claim 20: Following the discussion of claims 1-6, 10-11, 14, 18-19, and 23, Park et al. teach the use of an OptoSelect device with NanoPen chambers for screening antibody-producing CHO cells but do not teach the chip as comprising 1000-2000 chambers.
Le et al. teach single cell isolation and cloning using a OptoSelect 1750 nanofluidic chip comprising 1758 NanoPen chambers (See page 1, col. 2, full ¶2 and page 2, col. 2, full ¶3).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method of Park et al., modified by Roschke et al. and Buie et al., to substitute the nanofluidic chip taught by Le et al. Substitution of one known element for another known element is considered to be prima facie obvious, absent a showing that the substitution yields more than predictable results. See MPEP 2143(I)(B).
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JENNIFER S SPENCE, whose telephone number is 571-272-8590. The examiner can normally be reached M-F 8:30-5:30.
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/J.S.S./Examiner, Art Unit 1633
/CHRISTOPHER M BABIC/Supervisory Patent Examiner, Art Unit 1633
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