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
Claims 1-14 are pending and under consideration.
Priority
It is acknowledged that this application is a 371 of Internation Application No. PCT/US2021/061741 filed December 3, 2021, which claims the benefit of priority to U.S. Provisional Patent Appl. No. 63/120,979 filed December 3, 2020. The priority date has been established as December 3, 2020 for the pending claims.
Information Disclosure Statement
The Information Disclosure Statement filed on 05/30/2023 has been considered and entered by examiner.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-14 are rejected under 35 U.S.C. 101 because the claimed invention is directed to abstract idea without significantly more. The claim(s) recite(s):
“comparing deduced amino acid sequences of ii) with amino acid sequences of iii) to identify amino acid sequences of ii) that are the same as the amino acid sequences of iii), thereby identifying the Ag-specific VHH regions that are members of the mixed population of HCAbs” (claim 1 step iv);
“wherein identifying the deduced amino acid sequences of ii) that are the same as the amino acid sequences of iii) comprises a microprocessor implemented comparison of the amino acid sequences of ii) and iii)” (claim 5);
“wherein identifying the deduced amino acid sequences of ii) that are the same as the amino acid sequences of iii) comprises a microprocessor implemented comparison of the measured tandem mass spectra of ii) and the calculated tandem mass spectra of iii)” (claim 6).
The claim does not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claim recites additional elements that consist of well understood, routine, conventional activity already engaged in by the scientific community.
Under the broadest reasonable interpretation (BRI), the terms of the claims are presumed to have their plain meaning consistent with the specification as it would be interpreted by one of ordinary skill in the art. See MPEP 2111.01.
The claims are to processes, which fall in one of the statutory categories of invention. See MPEP 2106.03.
As explained in MPEP 2106.04(11) and the October 2019 Update, a claim “recites” a judicial exception when the judicial exception is “set forth” or “described” in the claim. The eligibility analysis comprises three-step tests: Step 1 determines whether the claim is directed to a process, machine, manufacture, or composition of matter. If the claim is directed to a statutory category, proceed to Step 2.
1) Step 2A Prong one: evaluating whether the claim recites a judicial exception (MPEP 2106.3); 2) Step 2A Prong two: evaluating whether the claim as a whole integrates the recited judicial exception into a practical application of the exception (MPEP 2106.4); 3) Step 2B: evaluating whether the claim as a whole amounts to significantly more than the recited exception (MPEP 2106.5).
The present claims are directed to a process so Step 1 is satisfied.
Step 2A, Prong 1 – does the claim recite a judicial exception? Yes, claim 1 recites an abstract idea. Specifically, the following limitations correspond to a judicial exception:
“comparing deduced amino acid sequences of ii) with amino acid sequences of iii) to identify amino acid sequences of ii) that are the same as the amino acid sequences of iii), thereby identifying the Ag-specific VHH regions that are members of the mixed population of HCAbs” under Broadest Reasonable Interpretation (BRI) include a mental process (an abstract idea) to evaluate a deduced amino acid sequences and to make a judgement based on the evaluation.
Similarly, under BRI, claims 5 and 6 also recite a mental process (an abstract idea).
Claim 1 recites a judicial exception, as set forth above, and the analysis must therefore proceed to Step 2A Prong Two.
Step 2A Prong Two: This part of the eligibility analysis evaluates whether the claim as a whole integrates the recited judicial exception into a practical application of the exception. This evaluation is performed by (a) identifying whether there are any additional elements recited in the claim beyond the judicial exception, and (b) evaluating those additional elements individually and in combination to determine whether the claim as a whole integrates the exception into a practical application. 2019 PEG Section III(A)(2), 84 Fed. Reg. at 54-55.
Besides the abstract idea, the claims recite the additional element of:
“i) introducing into a camelid an antigen such that a plurality of Ag-specific HCAbs is produced by the camelid”;
“ii) testing lymphocytes obtained from the camelid to determine polynucleotide sequences encoding the variable region (VHH) of a mixed population of HCAbs that includes the plurality of Ag-specific HCAbs and HCAbs that are not specific for the antigen (non-specific HCAbs), and deducing the amino acid sequences of the VHH regions of the Ag-specific HCAbs and non- specific HCAbs in the mixed population from the polynucleotide sequences”;
“iii) processing a sample from the camelid to separate Ag-specific HCAbs from non- specific HCAbs and determining the amino acid sequences of at least a portion of the VHH regions of the Ag-specific HCAbs”.
Under Step 2A, Prong 2, these additional elements are well understood, routine, conventional activity already engaged in by the scientific community. Therefore, these steps equate to insignificant extra-solution activity and are insufficient to integrate into a practical application. (Step 2A: YES).
Step 2B: This part of the eligibility analysis evaluates whether the claim as a whole amount to significantly more than the recited exception, i.e., whether any additional element, or combination of additional elements, adds an inventive concept to the claim. MPEP 2106.05. The previous considerations from Step 2A, Prong 2 are carried over and we re-evaluate the additional elements for their conventionality, both individually and in combination. In looking at the additional elements, they appear to be conventional both individually and in combination in light of prior art. For instance, Rout (Rout et al., US 2017/0212130 A1, Publication Date: July 27, 2017, cited in IDS of 05/30/2023) teaches “a method for identifying nanobodies that bind with specificity to an antigen (heavy chain only IgG class of antibodies (Ag-specific HCAbs)), the method comprising:
i) introducing into a camelid an antigen such that a plurality of Ag-specific HCAbs is produced by the camelid;
ii) testing lymphocytes obtained from the camelid to determine polynucleotide sequences encoding the variable region (VHH) of a mixed population of HCAbs that includes the plurality of Ag-specific HCAbs and HCAbs that are not specific for the antigen (non-specific HCAbs), and deducing the amino acid sequences of the VHH regions of the Ag-specific HCAbs and non-specific HCAbs in the mixed population from the polynucleotide sequences;
iii) processing a sample from the camelid to separate Ag-specific HCAbs from non-specific HCAbs and determining the amino acid sequences of at least a portion of the VHH regions of the Ag-specific HCAbs; and
iv) comparing deduced amino acid sequences of ii) with amino acid sequences of iii) to identify amino acid sequences of ii) that are the same as the amino acid sequences of iii), thereby identifying the Ag-specific VHH regions that are members of the mixed population of HCAbs (see claim 1).
Thus, these additional elements are directed to well understood, routine, conventional activity already engaged in by the scientific community and do not add an inventive concept to the instant claim.
Claim 2 recites additional elements “step iii) separating the Ag-specific HCAbs comprises removal of non-HCAb antibodies using Protein M, isolating Ag-specific HCAbs, digesting the isolated HCAbs using IdeS protease, separating digested fragments comprising segments of the VHH regions by gel electrophoresis to obtain separated fragments of the VHH regions from the gel, and using the separated segments of the VHH regions to determine the amino acid sequences of at least a portion of the Ag-specific HCAbs”. Rout teaches the method of instant claim 1. Grover (Grover et al., Science, Vol. 343, 656-661, Publication Date: 02/07/2014) teach Protein M preferentially bind antibody high chain, thus can be used for depleting conventional antibodies with light chain. Zhang (Zhang et al., Journal of Chromatography B, 1032 (2016) 172-181, Publication Date: 05/12/2016) and An (An et al., mAbs, 6:4, 879-893, Publication Date: August 2014, cited in IDS of 05/30/2023) shows that IdeS can generate different antibody fragments and provides several advantages compared with papain used in Rout. Rout teaches other steps recited by claim 2 (see more in 102 and 103 rejections). Taken together, the additional elements of claim 2 are directed to well understood, routine, conventional activity already engaged in by the scientific community and do not add an inventive concept to the instant claim.
Claims 3-14 recited additional elements which are well-known and routine method in the art, as evidenced by claims 2-13of Rout (Rout et al., US 2017/0212130 A1, Publication Date: July 27, 2017, cited in IDS of 05/30/2023), also see 103 rejection below.
Thus, claims 1-14 are directed to abstract idea without significantly more and properly rejected.
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.
Claim 1 is rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Rout (Rout et al., US 2017/0212130 A1, Publication Date: July 27, 2017, cited in IDS of 05/30/2023).
Rout teaches “a method for identifying nanobodies that bind with specificity to an antigen (heavy chain only IgG class of antibodies (Ag-specific HCAbs)), the method comprising:
i) introducing into a camelid an antigen such that a plurality of Ag-specific HCAbs is produced by the camelid;
ii) testing lymphocytes obtained from the camelid to determine polynucleotide sequences encoding the variable region (VHH) of a mixed population of HCAbs that includes the plurality of Ag-specific HCAbs and HCAbs that are not specific for the antigen (non-specific HCAbs), and deducing the amino acid sequences of the VHH regions of the Ag-specific HCAbs and non-specific HCAbs in the mixed population from the polynucleotide sequences;
iii) processing a sample from the camelid to separate Ag-specific HCAbs from non-specific HCAbs and determining the amino acid sequences of at least a portion of the VHH regions of the Ag-specific HCAbs; and
iv) comparing deduced amino acid sequences of ii) with amino acid sequences of iii) to identify amino acid sequences of ii) that are the same as the amino acid sequences of iii), thereby identifying the Ag-specific VHH regions that are members of the mixed population of HCAbs (see claim 1).
Thus, claim 1 of Rout anticipates the instant claim 1.
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.
Claim(s) 2-14 is/are rejected under 35 U.S.C. 103 as being unpatentable over Rout (Rout et al., US 2017/0212130 A1, Publication Date: July 27, 2017, cited in IDS of 05/30/2023) as applied to claim 1 above, and further in view of Grover (Grover et al., Science, Vol. 343, 656-661, Publication Date: 02/07/2014), Zhang (Zhang et al., Journal of Chromatography B, 1032 (2016) 172-181, Publication Date: 05/12/2016) and An (An et al., mAbs, 6:4, 879-893, Publication Date: August 2014, cited in IDS of 05/30/2023).
Rout teaches the method according to the instant claim 1 as set forth above. Rout also teaches separating the Ag-specific HCAbs comprising IgG fractionation and affinity purification; antigen-specific VHH fraction; LC-MS/MS, antigen-specific VHH spectra (Fig. 1).
Rout teaches VHH containing heavy chain antibody fraction was then affinity purified over antigen -coupled resin (a step of isolating Ag-specific HcAbs) ([0053]).
Rout teaches the antibodies were then digested with papain on-resin to cleave away the constant regions and leave behind the desired minimal VHH variable region fragments (Fig. 2b, and [0053]).
Rout teaches the antigen-bound VHH fragments were eluted and separated by SDS-PAGE (a gel-electrophoresis step), allowing the purification of the ~15 kDa VHH fragment away from Fab fragments derived from contaminating conventional antibodies as well as Fc fragments ([0053]).
Rout teaches the gel purified bands were then trypsin-digested and analyzed by liquid chromatography-MS and MS/MS (FIG. 2c, and [0053]).
However, Rout does not teach the specific steps recited by claim 2, such as removal of non-HCAb antibodies using Protein M, digesting the isolated HCAbs using IdeS protease.
Grover teaches that Protein M binds with high affinity to human and nonhuman immunoglobulin G, predominantly through attachment to the conserved portions of the variable region of the κ and λ light chains using conserved hydrogen bonds and salt bridges, from backbone atoms and conserved side chains, and some conserved van der Waals interactions (Abstract and the last paragraph of the article).
Grover teaches that Protein M binds may be particularly important for large scale purification of therapeutic antibodies (the last paragraph of the article).
Zhang teaches that IdeS cleaves the IgG heavy chain hinge region between the two glycine residues of the constant sequence ELLGGPS. And this cleavage leads to the release of the Fc domain (CH2-CH3) of the heavy chain (page 173, col. 1, para. 2; and Fig. 1).
Zhang teaches that the Fc domain (CH2-CH3) is about 25 kDa ((page 173, col. 1, para. 2; and Fig. 1).
Zhang teaches that IdeS has high cleavage specificity and simple digestion procedure (page 173, col. 1, para. 2).
An teaches when using papain to generate antibody fragments, the digestion condition needs to be carefully controlled to achieve high yields of the desired cleavage products and avoid over-digestion (page 880, col. 1, para. 3).
An teaches that IdeS is a recently discovered cysteine protease that cleaves at the hinge region of all IgG subclasses. IdeS digestion of an IgG1 molecule is illustrated in Figure 1. Compared with other proteases, IdeS provides a few advantages, including high site specificity, simple and robust digestion procedure, and high yield. Application of IdeS has been demonstrated in many literature reports on IgG1 and IgG2 molecules, as well as Fc fusion proteins (the bridging paragraph of cols. 1-2 on page 880).
It would have prima facie been obvious to modify the protocol of Rout and to take advantage of the differential specificity of Protein M for VHH fragments (without light chain) and conventional antibody (with light chain) for depleting conventional antibody with Protein M and obtaining exclusively VHH heavy chain antibodies; and to substitute papain with IdeS in the digestion step, because Zhang and An teaches that IdeS cleaves heavy chain at a very specific position. Compared to papain, IdeS provides several advantages such as high site specificity, simple and robust digestion procedure, and high yield. Given the teachings of reference, one of ordinary would have a reasonable expectation of success to modify the protocol of Rout to reach the claimed method, because Protein M can help to deplete conventional antibody and enrich VHH heavy chain antibody and IdeS is a better enzyme for generate different antibody fragments compared to papain. The motivation would be to develop a better and more reliable protocol to produce VHH heavy chain antibodies.
Regarding claim 3, Rout teaches that the determining the amino acid sequences of iii) comprises mass spectrometric analysis of the Ag-specific VHH regions (claim 2).
Regarding claim 4, Rout teaches that the determining the polynucleotide sequences of ii) comprises generating and sequencing a plurality of cDNA sequences that encode at least 100 unique VHH regions (claim 3). The range of at least 100 unique VHH regions overlaps at least 10,000 unique VHH regions as instantly claimed.
Regarding claim 5, Rout teaches identifying the deduced amino acid sequences of ii) that are the same as the amino acid sequences of iii) comprises a microprocessor implemented comparison of the amino acid sequences of ii) and iii) (claim 4).
Regarding claim 6, Rout teaches identifying the deduced amino acid sequences of ii) that are the same as the amino acid sequences of iii) comprises a microprocessor implemented comparison of calculated fragmentation patterns of deduced amino acid sequences of ii) and the fragmentation pattern of the amino acid sequences of iii) measured by tandem mass spectrometry (claim 5).
Regarding claim 7, Rout teaches separating Ag-specific antibodies from the non-specific antibodies comprises affinity purification of the Ag-specific antibodies using the antigen as an affinity capture agent (claim 6).
Regarding claim 8, Rout teaches the lymphocytes of ii) are obtained from bone marrow of the camelid, or are separated from a liquid biological sample obtained from the camelid (claim 7).
Regarding claim 9, Rout teaches the lymphocytes of ii) comprise B plasma cells (claim 8).
Regarding claim 10, Rout teaches the sample of iii) comprises serum from the camelid (claim 9).
Regarding claim 11, Rout teaches further comprising providing and introducing distinct expression vectors encoding distinct Ag-specific nanobodies into host cells, wherein the nanobody sequences are designed based on the deduced Ag-specific VHH regions allowing expression of the distinct Ag-specific nanobodies from the host cells, separating the Ag-specific nanobodies from the host cells, and testing the Ag-specific nanobodies for binding to the antigen (claim 10).
Regarding claim 12, Rout teaches the testing the Ag-specific nanobodies for binding to the antigen comprises testing for affinity and/or specificity for the antigen (claim 11).
Regarding claim 13, Rout teaches the testing comprises identifying one or more of the Ag-specific nanobodies that have a Kd in a sub-micromolar range (claim 12).
Regarding claim 14, Rout teaches the camelid is selected from camels, alpacas and llamas (claim 13).
Conclusion
No claims are allowed.
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/CHENG LU/Examiner, Art Unit 1642