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 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.
Claim 20 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 20 recites the limitation "the activity". There is insufficient antecedent basis for this limitation in the claim. The word "activity" is not defined in claim 1, upon which claim 20 depends. Because the claim introduced new element without prior reference or explanation, a one of ordinary skill in the art cannot determine with reasonable certainty the scope of protection. Hence, the metes and bounds of the claim are unascertainable.
Claims 21 depend from claim 20 and is therefore similarly rejected.
As per MPEP 2173: It is of utmost importance that patents issue with definite claims that clearly and precisely inform persons skilled in the art of the boundaries of protected subject matter. Therefore, claims that do not meet this standard must be rejected under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph as indefinite. Further, as per MPEP 2173.02: If the language of the claim is such that a person of ordinary skill in the art could not interpret the metes and bounds of the claim so as to understand how to avoid infringement, a rejection of the claim under 35 U.S.C. 112, second paragraph, would be appropriate. As currently written, the metes and bounds of the rejected claims are unascertainable for the reasons set forth above, thus the above claim(s) and all dependent claims are rejected under 35 USC 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph.
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.
Cox et al. and Dong et al.
Claim(s) 1-3, 6, 7, 10-12, 15, 20-23, 42, 43, 47, 69 is/are rejected under 35 U.S.C. 103 as being unpatentable over Cox et al. (US20180282721A1, 10/27/2017) in view of Dong et al (Sci Rep 10, 17806 (2020)).
Regarding claim 1, Cox discloses a method of generating a combinatorial nucleic acid library comprising: b) synthesizing the first plurality of polynucleotides, the second plurality of polynucleotides, and the third plurality of polynucleotides; and c) mixing the first plurality of polynucleotides, the second plurality of polynucleotides, and the third plurality of polynucleotides to form the combinatorial library of nucleic acids, wherein at least about 70% of a predicted diversity is represented. (e.g. “ (b) synthesizing the first plurality of polynucleotides and the second plurality of polynucleotides; and (c) mixing the first plurality of polynucleotides and the second plurality of polynucleotides to form the combinatorial library of nucleic acids, wherein at least about 70% of a predicted diversity is represented.” [paragraph 0008]).
However, Cox does not disclose a) designing predetermined sequences encoding for i) a first plurality of polynucleotides, wherein each polynucleotide of the first plurality of polynucleotides encodes for a first VHH antibody protein sequence or fragment thereof previously identified as a binder for a first epitope or first antigen; ii) a second plurality of polynucleotides, wherein each polynucleotide of the second plurality of polynucleotides encodes for a second VHH antibody sequence or fragment thereof previously identified as a binder for a second epitope or second antigen; and iii) a third plurality of polynucleotides, wherein each polynucleotide of the third plurality of polynucleotides encodes for a third VHH antibody sequence or fragment thereof previously identified as a binder for a third epitope or third antigen;
Dong discloses the identification and selection of multiple VHH antibodies that bind distinct epitopes of the SARS-CoV-2 S1 RBD, including VHHs classified into different epitope-binding groups based on competition and epitope mapping assays [Fig. 1-2, “Identification of VHHs binding to different epitopes of SARS-CoV-2 S1 protein RBD” section page 2]. Dong further teaches the construction of tri-specific nanobodies by combining predetermined VHH binders, each previously identified to bind a different epitope, into a single multi-specific antibody format [Fig. 5, Abstract, and “Tri-specific VHH-Fcs show potent S1 RBD binding and S/ACE2 blocking activity” section page 5].
Therefore, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine teachings of Cox and Dong because Cox discloses the design and synthesis of combinatorial nucleic acid libraries composed of predetermined sequences encoding antibody variants, including libraries that encode portions of antibodies, and are designed for downstream expression and activity screening. Cox further teaches that such libraries are non-random, are constructed from preselect polynucleotide sequences, and are generated with controlled representation of predicted diversity to enable efficient exploration and optimization of functional protein variants [paragraph 0008]. Dong discloses specific VHH antibody sequences can be previously identified and classified based on their binding to distinct epitopes, and further teaches that combining multiple epitope-specific VHH binders yields enhanced functional activity, such as improved binding and neutralization [page 1-2]. In view of Dong’s finding that epitope-diverse VHH provide functional advantages when combined, one of ordinary skill in the art would have a reasonable expectation of success and motivated to apply Cox’s combinatorial library methods to systematically encode and explore combinations of predetermined VHH binders, rather than limiting experimentations to a small number of constructs. Cox teaches generating combinatorial libraries encoding antibody sequences or fragments thereof for functional screening . Thus, Cox provides a predictable framework for encoding predetermined antibody sequences into combinatorial libraries with defined diversity, while Dong motivates selecting epitope distinct VHH binders as sequences to be encoded. The combination therefore represents a predictable and obvious use of prior art elements according to their established functions Hence, the proposed combination constitutes a predictable use of prior-art elements according to their established functions and would have been obvious to one of ordinary skill in the art at the time of filing. This reasoning is consistent with KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 — 97 (2007) (see MPEP § 2143, A).
Regarding claim 2, Cox and Dong disclose a method of generating a combinatorial nucleic acid library of claim 1 as discussed fully above and incorporated here. Cox further discloses assaying an activity for nucleic acids encoded by or proteins translated based on the combinatorial library of nucleic acids. (e.g. “(c) assaying an activity for nucleic acids encoded by or proteins translated based on the plurality of polynucleotides” [paragraph 0007]). Therefore, Cox teaches additional limitation of claim 2.
Regarding claim 3, Cox and Dong disclose a method of generating a combinatorial nucleic acid library of claim 2 as discussed fully above and incorporated here. Cox further discloses the activity is functional activity, structural stability, expression, specificity, or a combination thereof. (e.g. Downstream applications for selected variants are enzymatic activity, changes in cellular activity, for the treatment or prevention of a disease state, change in the proteins expression, binding affinity and stability. [paragraph 0055 and 0127]). Therefore, Cox teaches the additional limitation of claim 3
Regarding claim 6, Cox and Dong disclose a method of generating a combinatorial nucleic acid library of claim 1 as discussed fully above and incorporated here. Cox further discloses generating synthesized combinatorial nucleic acid libraries with highly controlled representation of sequence diversity, wherein a substantial portion of sequences are presented at frequencies closely clustered around a mean value. Specifically, Cox teaches that at least about 80% of nucleic acid sequences are represented within a define ranged relative to the mean frequency following amplification, showing deliberate control of variance and uniformity within the library [paragraph 0069].
Although Cox does not qualify distribution in term of “one standard deviation”, a person of person od ordinary skill in the art would have recognized that tightening the degree of variance around the mean , such as adjusting the representation from broader range unit (e.g. within a multiple of the mean [Cox et al., paragraph 0069]) to a narrower statistical measure (e.g. within one standard deviation), constitute a routine optimization. Cox teaches that controlling representation accuracy and variance is desirable for library performance, and selecting a narrower statistical threshold would have been predictable modification yielding no unexpected results. Therefore, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to adjust Cox’s disclosed distribution parameters to achieve a library wherein sequence representation falls within one standard deviation of the mean. "[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," (See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)).
Regarding claim 7, Cox and Dong disclose a method of generating a combinatorial nucleic acid library of claim 1 as discussed fully above and incorporated here. Dong discloses the identification and selection of multiple VHH antibody sequences that bind distinct epitope targets [Fig. 1-2, “Identification of VHHs binding to different epitopes of SARS-CoV-2 S1 protein RBD” section page 2], further disclose the construction of tri-specific VHH antibody constructs by combining predetermined VHH binders [Fig. 5, Abstract, and “Tri-specific VHH-Fcs show potent S1 RBD binding and S/ACE2 blocking activity” section page 5]. While Dong teaches combining VHHs directed to different epitopes of the same antigen, Dong establishes the motivation and technical feasibility of assembling multi-specific VHH constructs. Cox discloses antibody libraries comprising multi-specific antibody formats, including antibody and antibody fragments capable of recognizing different antigens. Cox further define antibodies to include single domain antibodies and multi-specific constructs such as diabodies recognizing two different antigens [paragraph 0059]. Cox therefore teaches that combinatorial antibody libraries are not limited to a single antigen and can be designed to target multiple antigens. A person of ordinary skill in the art would have been motivated to apply Cox’s teaching regarding multi-antigen antibody format to the tri-specific VHH constructs taught by Dong, as a predictable variation of the disclosed multi-specific antibody design. Extending Dong’s epitope-diverse VHH combinations to bind different antigens, as taught by Cox, represents a routine and predictable modification within established scope of combinatorial antibody design. Therefore, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to generate combinatorial libraries encoding tri-specific VHH antibodies, wherein one or more of the binders recognize different antigens. Therefore, Cox and Dong teach the additional limitation of Claim 7.
Regarding claim 10, Cox and Dong disclose a method of generating a combinatorial nucleic acid library of claim 7 as discussed fully above and incorporated here. Cox further discloses one or more of the first antigen, second antigen, or third antigen is a G protein. (e.g. the proteins selected for optimizations includes enzyme, transporter proteins, G-protein coupled receptors [paragraph 0127]). Therefore, Cox teaches the additional limitation of Claim 10.
Regarding claim 11, Cox and Dong disclose a method of generating a combinatorial nucleic acid library of claim 1 as discussed fully above and incorporated here. Dong further discloses one or more of the first antigen, second antigen, or third antigen are the same antigen (e.g. The antigen is SARS-CoV-2 S1 protein [abstract]). Therefore, Cox teaches the additional limitation of Claim 11.
Regarding claim 12, Cox and Dong disclose a method of generating a combinatorial nucleic acid library of claim 1 as discussed fully above and incorporated here. Dong further discloses one or more of the first epitope, second epitope, and third epitope is present on a single target protein. (e.g. The target protein is SARS-CoV-2 S1 protein [abstract]). Therefore, Cox teaches the additional limitation of Claim 12.
Regarding claim 15, Cox and Dong disclose a method of generating a combinatorial nucleic acid library of claim 1 as discussed fully above and incorporated here. Cox further discloses one or more of the first epitope, second epitope, and third epitope is present on a G protein. (e.g. the proteins selected for optimizations includes enzyme, transporter proteins, G-protein coupled receptors [paragraph 0127]). Therefore, Cox teaches the additional limitation of Claim 15.
Regarding claim 20, Cox and Dong disclose a method of generating a combinatorial nucleic acid library of claim 1 as discussed fully above and incorporated here. Cox further discloses the activity is cellular activity. (e.g. changes in activity, whether increased or decreased, are linked to specific cellular functions. These functions encompass a wide range of physiological processes, including but not limited to growth, reproduction, adhesion, apoptosis (cell death), migration, and metabolic activity. They also involve energy production, oxygen consumption, intracellular signaling, and the cellular response to oxidative stress [paragraph 0061]). Therefore, Cox teaches the additional limitation of Claim 20.
Regarding claim 21, Cox and Dong disclose a method of generating a combinatorial nucleic acid library of claim 20 as discussed fully above and incorporated here. Cox further the cellular activity comprises reproduction, growth, adhesion, death, migration, energy production, oxygen utilization, metabolic activity, cell signaling, response to free radical damage, or any combination thereof. (e.g. changes in activity, whether increased or decreased, are linked to specific cellular functions. These functions encompass a wide range of physiological processes, including but not limited to growth, reproduction, adhesion, apoptosis (cell death), migration, and metabolic activity. They also involve energy production, oxygen consumption, intracellular signaling, and the cellular response to oxidative stress [paragraph 0061]). Therefore, Cox teaches the additional limitation of Claim 21.
Regarding claim 22, Cox and Dong disclose a method of generating a combinatorial nucleic acid library of claim 1 as discussed fully above and incorporated here. Cox further discloses at least 10,000 polynucleotides are synthesized [paragraph 0008]. Therefore, Cox teaches the additional limitation of Claim 22.
Regarding claim 23, Cox and Dong disclose a method of generating a combinatorial nucleic acid library of claim 1 as discussed fully above and incorporated here. Cox further discloses at least about 90% of a predicted diversity is represented [paragraph 0007]. Therefore, Cox teaches the additional limitation of Claim 23.
Regarding claim 42, Cox discloses a combinatorial nucleic acid library, which comprises of Defined sequences comprising: : (i) a first set of polynucleotides, where each member contains a variation relative to a peptide sequence; and (ii) a second set of polynucleotides, in which each member also encodes a variant relative to a peptide sequence. [paragraph 0008]. However, Cox does not disclose a third set of polynucleotides and that the polynucleotides encodes for VHH antibody sequences.
Dong discloses the identification and selection of multiple VHH antibodies that bind distinct epitopes of the SARS-CoV-2 S1 RBD, including VHHs classified into different epitope-binding groups based on competition and epitope mapping assays [Fig. 1-2, “Identification of VHHs binding to different epitopes of SARS-CoV-2 S1 protein RBD” section page 2]. Dong further teaches the construction of tr-specific nanobodies by combining predetermined VHH binders, each previously identified to bind a different epitope, into a single multi-specific antibody format [Fig. 5, Abstract, and “Tri-specific VHH-Fcs show potent S1 RBD binding and S/ACE2 blocking activity” section page 5].
Therefore, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine teachings of Cox and Dong because Cox discloses the design of combinatorial nucleic acid libraries composed of predetermined sequences encoding antibody variants, including libraries that encode portions of antibodies, and are designed for downstream expression and activity screening. Cox further teaches that such libraries are non-random, are constructed from preselect polynucleotide sequences, and are generated with controlled representation of predicted diversity to enable efficient exploration and optimization of functional protein variants [paragraph 0008]. Dong discloses that specific VHH antibody sequences can be previously identified and classified based on their binding to distinct epitopes, and further teaches that combining multiple epitope-specific VHH binders yields enhanced functional activity, such as improved binding and neutralization [page 1-2]. In view of Dong’s finding that epitope-diverse VHH provide functional advantages when combined, one of ordinary skill in the art would have a reasonable expectation of success and motivated to apply Cox’s combinatorial library methods to systematically encode and explore combinations of predetermined VHH binders, rather than limiting experimentations to a small number of constructs. Cox teaches generating combinatorial libraries encoding antibody sequences or fragments thereof. Thus, Cox provides a predictable framework for encoding predetermined antibody sequences into combinatorial libraries with defined diversity, while Dong motivates selecting epitope distinct VHH binders as sequences to be encoded. The combination therefore represents a predictable and obvious use of prior art elements according to their established functions Hence, the proposed combination constitutes a predictable use of prior-art elements according to their established functions and would have been obvious to one of ordinary skill in the art at the time of filing. This reasoning is consistent with KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 — 97 (2007) (see MPEP § 2143, A).
Regarding claim 43, Cox and Dong disclose a method of generating a combinatorial nucleic acid library of claim 1 as discussed fully above and incorporated here. Cox further discloses generating synthesized combinatorial nucleic acid libraries with highly controlled representation of sequence diversity, wherein a substantial portion of sequences are presented at frequencies closely clustered around a mean value. Specifically, Cox teaches that at least about 80% of nucleic acid sequences are represented within a define ranged relative to the mean frequency following amplification, showing deliberate control of variance and uniformity within the library [paragraph 0069].
Although Cox does not qualify distribution in term of “one standard deviation”, a person of person od ordinary skill in the art would have recognized that tightening the degree of variance around the mean , such as adjusting the representation from broader range unit (e.g. within a multiple of the mean [Cox et al., paragraph 0069]) to a narrower statistical measure (e.g. within one standard deviation), constitute a routine optimization. Cox teaches that controlling representation accuracy and variance is desirable for library performance, and selecting a narrower statistical threshold would have been predictable modification yielding no unexpected results. Therefore, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to adjust Cox’s disclosed distribution parameters to achieve a library wherein sequence representation falls within one standard deviation of the mean. "[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," (See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)).
Regarding claim 47, Cox and Dong disclose a method of generating a combinatorial nucleic acid library of claim 42 as discussed fully above and incorporated here. Cox further discloses one or more of the first epitope, second epitope, and third epitope is present on a G protein. (e.g. the proteins selected for optimizations includes enzyme, transporter proteins, G-protein coupled receptors [paragraph 0127]). Therefore, Cox teaches the additional limitation of Claim 47.
Regarding claim 69, Cox discloses a combinatorial sequence library comprising: Defined sequences comprising: (i) a first set of polynucleotides, where each member contains a variation relative to a peptide sequence; and (ii) a second set of polynucleotides, in which each member also encodes a variant relative to a peptide sequence. [paragraph 0008]. However, Cox does not disclose a third set of polynucleotides and that the polynucleotides encodes for VHH antibody sequences.
Dong discloses the identification and selection of multiple VHH antibodies that bind distinct epitopes of the SARS-CoV-2 S1 RBD, including VHHs classified into different epitope-binding groups based on competition and epitope mapping assays [Fig. 1-2, “Identification of VHHs binding to different epitopes of SARS-CoV-2 S1 protein RBD” section page 2]. Dong further teaches the construction of tr-specific nanobodies by combining predetermined VHH binders, each previously identified to bind a different epitope, into a single multi-specific antibody format [Fig. 5, Abstract, and “Tri-specific VHH-Fcs show potent S1 RBD binding and S/ACE2 blocking activity” section page 5].
Therefore, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine teachings of Cox and Dong because Cox discloses the design of combinatorial nucleic acid libraries composed of predetermined sequences encoding antibody variants, including libraries that encode portions of antibodies, and are designed for downstream expression and activity screening. Cox further teaches that such libraries are non-random, are constructed from preselect polynucleotide sequences, and are generated with controlled representation of predicted diversity to enable efficient exploration and optimization of functional protein variants [paragraph 0008]. Dong discloses that specific VHH antibody sequences can be previously identified and classified based on their binding to distinct epitopes, and further teaches that combining multiple epitope-specific VHH binders yields enhanced functional activity, such as improved binding and neutralization [page 1-2]. In view of Dong’s finding that epitope-diverse VHH provide functional advantages when combined, one of ordinary skill in the art would have a reasonable expectation of success and motivated to apply Cox’s combinatorial library methods to systematically encode and explore combinations of predetermined VHH binders, rather than limiting experimentations to a small number of constructs. Cox teaches generating combinatorial libraries encoding antibody sequences or fragments thereof. Thus, Cox provides a predictable framework for encoding predetermined antibody sequences into combinatorial libraries with defined diversity, while Dong motivates selecting epitope distinct VHH binders as sequences to be encoded. The combination therefore represents a predictable and obvious use of prior art elements according to their established functions Hence, the proposed combination constitutes a predictable use of prior-art elements according to their established functions and would have been obvious to one of ordinary skill in the art at the time of filing. This reasoning is consistent with KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 — 97 (2007) (see MPEP § 2143, A).
Cox et al., Dong et al., and Sato et al.
Claim(s) 4 and 5 is/are rejected under 35 U.S.C. 103 as being unpatentable over Cox et al. (US20180282721A1, 10/27/2017) in view of Dong et al. (Sci Rep 10, 17806 (2020)), and Sato et al. (WO2021061842A1, disclosed in IDS)
Regarding claim 4, Cox and Dong disclose a method of generating a combinatorial nucleic acid library of claim 3 as discussed fully above and incorporated here. However, Cox and Dong do not disclose the structural stability is thermal stability.
Sato discloses the structural stability is thermal stability. (e.g. Antibody libraries and their specific regions are screened for functional activity, structural stability (e.g., thermal and pH), expression, specificity, and proper folding [paragraph 0078].
Therefore, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to evaluate thermal stability as part of structural stability assessment of the combinatorial antibody libraries of Cox and Dong because thermal stability is a well-established and routine measured parameter for antibody developability and functionality. Incorporating thermal stability testing represent a predictable variation of the screening criteria already taught by Cox and Dong and would have been expected to yield useful information regarding antibody performance and suitability for downstream applications. As of the application’ s effective filing date, one of ordinary skill in the art would have had a reasonable expectation of success and motivated to include Sato’s assessing thermal stability in the method of Cox and Dong. This reasoning is consistent with KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 — 97 (2007) (see MPEP § 2143, E).
Regarding claim 5, Cox and Dong disclose a method of generating a combinatorial nucleic acid library of claim 3 as discussed fully above and incorporated here. However, Cox and Dong do not disclose the structural stability is pH stability.
Sato discloses the structural stability is pH stability. (e.g. Antibody libraries and their specific regions are screened for functional activity, structural stability (e.g., thermal and pH), expression, specificity, and proper folding [paragraph 0078].
Therefore, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to evaluate pH stability as part of structural stability assessment of the combinatorial antibody libraries of Cox and Dong because pH stability is a well-established and routine measured parameter for antibody developability and functionality. Incorporating pH stability testing represent a predictable variation of the screening criteria already taught by Cox and Dong and would have been expected to yield useful information regarding antibody performance and suitability for downstream applications. As of the application’ s effective filing date, one of ordinary skill in the art would have had a reasonable expectation of success and motivated to include Sato’s assessing pH stability in the method of Cox and Dong. This reasoning is consistent with KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 — 97 (2007) (see MPEP § 2143, E).
Cox et al., Dong et al., and Corti et al.
Claim(s) 16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Cox et al. (US20180282721A1, 10/27/2017) in view of Dong et al. (Sci Rep 10, 17806 (2020)), and Corti et al. (WO2021203053A1, 04/02/2021)
Regarding claim 16, Cox and Dong disclose a method of generating a combinatorial nucleic acid library of claim 1 as discussed fully above and incorporated here. Cox and Dong do not disclose one or more of the first epitope, second epitope, and third epitope is present on more than one target protein.
Corti discloses antibodies and antigen-binding fragments that recognize a conserved epitope region represent on the SARS CoV-2 surface glycoprotein receptor binding domain (RBD), wherein the same epitope shared across multiple coronaviruses target proteins, including SARS CoV-2 and other SARS-related coronaviruses (e.g., Urbani, CHUK-1, GZ02, HC_SZ_61_03, A031G, WIV1 SARS-like bat) [Line 1-6 page 14]. Thus, Corti teaches that a single epitope sequence can be present on more than one target protein.
Therefore, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to incorporate the Corti’s teaching into combinatorial library method of Donga and Cox, because selecting epitopes that are conserved across multiple target proteins is a well-established strategy for increasing breadth of binding and functional utility of antibody libraries. Applying Cox’s combinatorial library framework and Dong’s epitope-specific VHH selection to conserved epitopes taught by Corti represents a predictable and routine modification, yielding antibody binders capable of recognizing the same epitope on more than one target protein. As of the application’ s effective filing date, one of ordinary skill in the art would have had a reasonable expectation of success and motivated to generate combinatorial sequence library where in one or more epitopes is presented on more than one protein target. This reasoning is consistent with KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 — 97 (2007) (see MPEP § 2143, E).
Conclusion
No claims are allowed
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Khai Quynh Tien Pham whose telephone number is (571)272-6998. The examiner can normally be reached M-T, 9-4 ET.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Heather Calamita can be reached at (571) 272-2876. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/KHAI QUYNH TIEN PHAM/Examiner, Art Unit 1684
/JEREMY C FLINDERS/Primary Examiner, Art Unit 1684