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 .
Priority
This application is a 371 of PCT/US2022/040350 filed 08/15/2022. PCT/US2022/040350 has PRO 63/354,010 filed 06/21/2022 and PRO 63/232,948 filed 08/13/2021. All claims are examined using the earlies filing date.
Claim Status
Claims 1-25 are pending and under examination. Claim 1 is the only independent claim.
Claim Objections
Claim 21 objected to because of the following informalities: Typographical error.
Claim 21 recites “spike protein of SARS-CoV-2 or a SARS-CiV-2 variant” and should recite “spike protein of SARS-CoV-2 or a SAR-CoV-2 variant.”
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 14 and 25 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.
Claim 14 recites the limitation "the combined LCDR/HCDR library" in line 1. There is insufficient antecedent basis for this limitation in the claim.
Claim 25 recites the limitation “the protein” in line 1. There is insufficient antecedent basis for this limitation in the claim.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 25 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 25 illogically depends from claim 1, reciting “the protein of claim 1,” but claim 1 is a method claim and not a protein claim. As such, Claim 25 fails to further limit the subject matter of the claim upon which it depends. Claim 25 should likely depend from claim 24, which recites “A protein identified by the method of claim 1”. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Interpretation
Claim 25 is being examined as if the claim were dependent upon claim 24 which would clear the rejections for the lack of antecedent basis and dependency issues stated above.
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 1-17, and 24-25 are rejected under 35 U.S.C. 102(a)(1)/102(a)(2) as being anticipated by Crea (US 2008/0214406 A1, published Sep. 4, 2008).
In regards to claim 1, Crea teaches “A method for identifying an optimized protein, the method comprising: (a) selecting targeted libraries against a target antigen using a first set of selection conditions to select a pool of binders in each library.” Crea discloses constructing separate CDR-targeted libraries, for example, a three-CDR heavy-chain library and three-CDR light-chain library, each of which is subjected to selection against a target antigen prior to any combination steps (see Abstract, [0139], [0110]-[0111] (describing separate VH and VL CDR library construction). Example 2 discloses the selection protocol applied to such libraries: yeast cells displaying the library are incubated with biotinylated antigen, and close binding the antigen are recovered via magnetic bead separation by regrowth (see [0121]-[0122]). This reads on “selecting targeted libraries against a target antigen using a first set of selection conditions.”
In regards to step “(b) combining the selected libraries into one or more libraries”, Crea discloses that after screening the separate heavy and light chain CDR libraries, the beneficial mutations of the heavy and light chain libraries can be further combined into a single library (see [0139]).
In regards to step “(c) selecting the combined library against the target antigen using a second set of selection conditions to identify at least one protein having an optimized functional profile,” Crea discloses a three-round selection scheme in which the antigen concentration is progressively lowered across rounds, from 10 nM to 0.5 nM to 0.1 nM, with binding/fitness of the recovered clones evaluated by FACS after each round (see [0123]). Screened clones are characterized by EC50 and K off values relative to a wild-type reference, and clones with improved (lower EC50, slower K off) binding are identified as having an enhanced or optimized functional property (see [0123], [0127]-[0129], [0132]-[0133]). This reads on selecting the combined library under a second, further set of selection conditions to identify a protein with an optimized functional profile.
In regards to claim 2, Crea discloses library members are single-chain antibody fragments (ScFv; see Abstract [0035], [0078]-[0079]).
In regards to claim 3, Crea discloses detailed library construction protocols preceding the selection example (see [0062]-[0072], [0099]-[0104]).
In regards to claim 4, Crea discloses in Example 2, that across the three sequential selection rounds, the antigen concentration used to challenge the library is progressively decrease, from 10 nM to 0.5 nM to 0.1 nM (see [0122]). A lower antigen concentrations selects more stringently for higher-affinity binders, since only clones with sufficiently high affinity will capture antigen at the reduced concentration. This reads on second selection round being more stringent that the first. Because claim is anticipated as set forth above, and Crea’s library members are ScFv antibody fragments throughout claim 4 is likewise anticipated.
In regards to claim 5, 8-13, Crea discloses target libraries that are expressly CDR libraries, VH and VL CDR1, CDR2, and CDR3 libraries, as well as each combination of only VH alone, VL alone, or both VH and V-L mixed together (see [0111], [0139]).
In regards to claim 6, Crea’s disclosed progressive reduction in antigen concentration across selection rounds (10 nM to 0.5 nM to 0.1 nM) reads on this limitation directly (see [0122]).
In regards to claim 7, Crea teaches screening for improved binding affinity (EC50) and dissociation kinetics (K off) relative to a defined reference standard (see [0127]-[0129]).
In regards to claims 14 and 15, Crea teaches screening libraries with a progressive reduction in antigen concentration across multiple selection rounds, each more stringent than the previous round (see [0122], [0127]-[0129]).
In regards to claim 16, Crea expressly lists phage display among the suitable expression/display systems for the claimed libraries alongside cell-free, bacterial, and yeast display systems (see [0076]), reading on this limitation notwithstanding that the working examples use yeast display.
In regards to claim 17, Crea expressly discloses use of single overlap extension PCR (SOE-PCR) to assemble and combine separately generated CDR fragments into a full-length gene (see [0022], [0100]-[0103]).
In regards to claims 24 and 25, Crea teaches identifying a protein using their methods, which correspond to claim 1. Using their method Crea identified an improved anti-ovalbumin antibody (see Fig. 14).
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.
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 1-18 and 24-25 are rejected under 35 U.S.C. 103 as being unpatentable over Crea (US 2008/0214406 A1, published Sep 4, 2008) as applied to claim 1-17 and 24-25 above, and further in view of Bobrowicz (US 2016/0077105 A1, published Mar. 17, 2016).
In regards to claim 18, Crea discloses the method of claim 1, for which claim 18 depends, as set forth in the rejection above, including construction of separate CDR targeted libraries, selection of each against a target antigen, combination of the selected libraries, and selection of the combined library to identify a protein having an optimized functional profile (see Crea [0110]-[0139]). Crea does not expressly disclose a step designed to reduce identification of a protein that is polyreactive.
Bobrowicz, however, is directed to the same field of endeavor , selection and screening of display library derived polypeptides, including antibody fragments, and discloses that such libraries commonly yield polyspecific (polyreactive) binders as an undesired byproduct of affinity based selection, and that this problem can be addressed by incorporating a counter selection step, using soluble membrane proteome preparations (SMPs) or soluble cytosolic proteome preparations (SCPs) as counter-selection reagents, into the library selection scheme (see Bobrowicz Figs. 7-8, 15). Bobrowicz’s Example 4, demonstrates this counter selection integrated across multiple selection rounds (R1-R4) of a genotype-phenotype display library, in parallel with antigen directed affinity selection, to enrich for non-polyspecific, developable polypeptides while preserving sequence diversity in the selected output (see Bobrowicz [0323]-[0332]).
It would have been obvious to a person of ordinary skill in the art, before the effective filling date of the claimed invention, to incorporate a polyreactive counter-selection step, as taught by Bobrowicz, into the library selection method of Crea. A person of ordinary skill would have been motivated to do so because polyspecific/polyreactive binders are recognized, undesirable byproducts of antibody library selection generally (as Bobrowicz explains at length, see Bobrowicz [0008]), and because Crea’s own stated goal, identification of proteins having “improved” or “enhanced” functional properties suitable for further development, would be furthered, not hindered by removing polyreactive candidates that are typically disfavored for downstream development due to poor specificity and development profiles (see Crea [0008]). Both references are in the same field (antibody display library selection) and address the same general problem (identifying developable, high-quality binders from a diverse library), such that a person of ordinary skill would have had a reasonable expectation of success in combining Bobrowicz’s counter-selection step with Crea’s library construction, combination, and selection scheme, and the combination amounts to no more than the use of known techniques to improve a similar method in the same way.
Claims 1-25 are rejected under 35 U.S.C. 103 as being unpatentable over Crea (US 2008/0214406 A1, published Sep 4, 2008) in view of Bobrowicz (US 2016/0077105 A1, published Mar. 17, 2016) as applied to claim 1-18 and 24-25 above, and further in view of Bertoglio et al. (“SARS-CoV-2 neutralizing human recombinant antibodies selected from pre-pandemic healthy donors binding at RBD-ACE2 interface”, Nat. Commun. 12, 1577 (2021), published Mar. 11, 2021)
Crea discloses the methods of claims 1 and 5 from which claims 19-23 depend, using ovalbumin as the model target antigen, as set forth above. Crea does not disclose a viral target antigen, let alone SARS-CoV-2, spike, or RBD antigen specifically.
Bertoglio, discloses use of phage display to select anti-SARS-CoV-2 spike antibodies from naïve human antibody gene libraries (HAL9/10), identifying antibodies against the S1 subunit of the SARS-CoV-2 spike protein, seventeen of which bind specifically to the receptor-binding domain (RBD) of the spike protein and block the RBD-ACE2 interaction (see Bertoglio Abstract, and throughout). Bertoglio’s selection methodology uses the same general phage display panning approach, immobilized target antigen, sequential rounds of panning, and enrichment for antigen specific binders (see Bertoglio pg. 2, right col. last para. – pg. 3 left col. 3rd para.), as is generically disclosed as a suitable display platform by Crea (see Crea [0076])
It would have been prima facie obvious to one of ordinary skill in the art at the time of filing to apply the CDR library selection and combination method of Crea using a SARS-CoV-2 spike or RBD antigen, as disclosed in Bertoglio, as the target antigen in place of Crea’s model antigen, ovalbumin. A person of ordinary skill in the art would have been motivated to make this substitution because Crea’s method is expressly disclosed as generally applicable to identifying improve-affinity binding molecule against “a chosen antigen” (see Crea [0111]) and is not limited to any particular antigen or antigen class such that selection of a specific antigen of interest, including viral antigens of significant public health importance such as SARS-CoV-2 spike/RBD, is simply an application of a known method to a known, art recognized target.
This combination reads on claim 19 (viral antigen), claim 20 (Coronavirus-associated antigen), claim 21, (SAR-CoV-2 or variant associated antigen), claim 22 (spike protein of SARS-CoV-2 or variant) and claim 23 (RBD of SARS-CoV-2 or variant), each of which merely narrows the identity of the target antigen to be used in Crea’s otherwise fully disclosed method.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Matthew H Raymonda whose telephone number is (703)756-5807. The examiner can normally be reached Monday - Friday 10:00 am - 4:00 pm.
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/MATTHEW HAROLD RAYMONDA/Examiner, Art Unit 1684
/AARON A PRIEST/Primary Examiner, Art Unit 1681
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