DETAILED ACTION
Preliminary Amendment filed on 04/12/2024 is acknowledged. Claims 17, 19-21, 24-35 and 37-50 are cancelled. Claims 1-16, 18, 22-23,36 and 51 are pending in the application and are considered on merits.
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 8 is 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 8 recites the limitation "the monoclonal antibodies" in line 1. There is insufficient antecedent basis for this limitation in the claim.
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.
Claim(s) 1-4, 15, 36 and 51 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Kim et al. (Analytical Chemistry, 2011) (Kim).
Regarding claim 1, Kim teaches a method for analyzing proteins in a sample using asymmetrical flow field flow fractionation (A4F) and mass spectrometry (MS) (abstract), wherein the method comprises the steps of:
(a) providing a liquid sample comprising proteins in an ammonium salt buffer (p. 8654, par 2);
(b) fractionating the liquid sample by an A4F instrument to provide a fractionated liquid sample (p. 8654, par 2); and
(c) sending a microflow of the fractionated liquid sample to a mass spectrometer for spectral analysis (Fig. 1a, p. 8654, par 2).
Regarding claim 2, Kim teaches that the method according to claim 1, further comprising characterizing the proteins based upon the spectral analysis (abstract, p. 8654, par 2).
Regarding claim 3, Kim teaches that wherein the microflow is provided by using a tee to split the sample flow from the A4F (p.8654, par 2).
Regarding claim 4, Kim teaches that wherein A4F instrument has a short channel (p. 8654, par 3).
Regarding claim 15, Kim teaches that wherein the method can characterize protein complexes (p.8657, par 3).
Regarding claim 36, Kim teaches wherein the microflow is within the recited flow-rate ranges.
Kim states:
“The AFlFFF outflow stream was first split to reduce the feeding flow rate (from 12 to 4 μL/min) using a micro-Tee” (p. 8654, par 2).
Kim further states:
“The final flow rate at the ESI-MS was 5 μL/min.” (p. 8654, par 2).
Thus, Kim expressly provides a 4 μL/min microflow of the fractionated AF4 outflow being fed toward the ESI-MS. The claimed alternatives include 0.5–10 μL/min, 0.75–8 μL/min, 1–6 μL/min, 1.25–5 μL/min, and 1.5–4 μL/min, each of which encompasses Kim's expressly disclosed 4 μL/min and 5 μL/min flow rate.
Regarding claim 51, Kim discloses a system capable of performing a method according to claim 1 and the description contained herein (Fig. 1a, p. 8654, par 2).
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.
Claim(s) 5-10 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kim et al. (Analytical Chemistry, 2011) (Kim) in view of Masiello et al. (US 2017/0129966) (Masiello).
Regarding claim 5, Kim does not specifically teach that wherein the proteins are Fc-containing proteins.
However, Masiello teaches wherein the proteins are Fc-containing proteins. Masiello states:
“methods … for the production of antibodies containing an Fc fragment”
and teaches isolating and purifying “the Fc fragment from such antibodies” (par [0038).
Masiello further defines an Fc fragment as “the portion of an immunoglobulin that interacts with cell surface Fc receptors” and states that it may comprise the CH2 and CH3 heavy-chain constant domains (par [0040).
Therefore, at the time of the effective filing date, it would have been obvious to a person of ordinary skill in the art to modify the protein-analysis method taught by Kim to analyze the Fc-containing antibodies and antibody fragments taught by Masiello, motivated to provide further analysis and characterization of such Fc-containing proteins by mass spectrometry, as expressly contemplated by Masiello.
Regarding claim 6, Masiello teaches wherein the Fc-containing proteins are antibodies, expressly disclosing “antibodies containing an Fc fragment” (par [0038]).
Regarding claim 7, Masiello teaches wherein the antibodies are monoclonal antibodies, stating:
“The term ‘antibodies’ also encompasses different types of antibodies, e.g., recombinant antibodies, monoclonal antibodies, humanized antibodies or chimeric antibodies” (par [0048]).
Masiello further states that the disclosed human antibodies “can be monoclonal antibodies” (par [0051]).
Regarding claim 8, Masiello teaches multispecific antibodies, stating:
“the antibodies are bispecific or multispecific antibodies”
and further:
“the antibodies of the present disclosure can be modified to be in the form of a bispecific antibody, or a multispecific antibody” (par [0046]).
Because Masiello's disclosed antibodies expressly include monoclonal antibodies (par [0048]) and Masiello further teaches that the disclosed antibodies may be modified into multispecific antibodies (par [0046]), it would have been obvious to use a monoclonal antibody in multispecific form.
Regarding claim 9, Masiello teaches wherein the Fc-containing proteins are antibody fragments. Masiello teaches isolation of an Fc fragment from an antibody and explains:
“the enzyme does not digest the Fc fragment but separates the Fc fragment from the additional fragment of the antibody.”
Masiello further states that digestion produces “an Fc fragment and an additional fragment” (par [0065]).
Thus, Masiello's Fc fragment is both an antibody fragment and an Fc-containing protein.
Regarding claim 10, Masiello teaches wherein the Fc-containing proteins are antibody fragments that lack Fv regions. Masiello teaches that an Fc fragment comprises heavy-chain constant domains, expressly including CH2 and CH3 (par [0040]). In contrast, Masiello separately identifies VH and VL as the antibody's variable regions and explains that:
“The variable regions of the heavy and light chains contain a binding domain that interacts with an antigen.” (par [0045]).
Masiello further teaches enzymatically separating the Fc fragment from the additional antibody fragment, where the additional fragment can be Fab, Fab′, F(ab′)2, or scFv (par [0065]). Thus, Masiello's isolated Fc fragment comprises the constant Fc portion rather than the VH/VL variable regions forming an Fv region and therefore corresponds to an antibody fragment lacking Fv regions.
Claims 11-13, 16, and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Kim et al. (Analytical Chemistry, 2011) (Kim) in view of Liu et al. (US 2020/0072844, IDS) (“Liu”).
Regarding claim 11, Kim does not specifically teach that wherein the Fc-containing proteins are Fc-fusion proteins.
Liu teaches wherein the Fc-containing proteins are Fc-fusion proteins, stating:
“the protein in the complexes is a recombinant protein that contains an Fc moiety and another domain, (e.g., an Fc-fusion protein).” (par [0077]).
Therefore, at the time of the effective filing date, it would have been obvious to a person of ordinary skill in the art to modify the A4F-MS protein-analysis method taught by Kim to analyze the Fc-fusion proteins and protein complexes taught by Liu, motivated to improve the characterization of such therapeutic proteins and protein complexes using A4F separation followed by protein analysis.
Regarding claim 12, Liu teaches wherein the Fc-containing proteins are receptor Fc-fusion proteins, stating:
“an Fc-fusion protein is a receptor Fc-fusion protein, which contains one or more extracellular domain(s) of a receptor coupled to an Fc moiety” (par [0077])
Regarding claim 13, Liu teaches wherein the receptor Fc-fusion proteins are trap proteins, stating:
“an Fc-fusion protein is a TRAP protein”
and expressly identifying an IL-1 Trap and a VEGF Trap, including aflibercept (par [0077]).
Regarding claim 16, Liu teaches wherein the protein complexes are homogeneous or heterogeneous. In particular, Liu expressly teaches heterogeneous complexes, stating that therapeutic monoclonal antibodies or fusion proteins binding soluble multimeric targets can produce:
“large heterogeneous complexes”
and describes fractionating heterogeneous protein complexes using A4F. (par [0056]).
Because claim 16 recites the alternatives “homogeneous; or heterogeneous,” Liu's express disclosure of heterogeneous protein complexes satisfies the claimed alternative.
Regarding claim 18, Liu teaches wherein the protein complexes comprise receptor Fc-fusion proteins and ligands, which is one of the alternatives recited in claim 18. Liu teaches that the complexes may “comprise or consist of antibody:ligand complexes or fusion protein:ligand complexes.” (par [0056]). Liu further specifically teaches receptor Fc-fusion proteins and states that such proteins contain receptor chains that:
“bind to either a single ligand or multiple ligands.” (par [0077]).
Thus, Liu teaches the claimed alternative of a protein complex comprising a receptor Fc-fusion protein and ligand.
Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over Kim et al. (Analytical Chemistry, 2011) (Kim) in view of Franklin (US 2021/0214733).
Regarding claim 14, Kim teaches the method of claim 1 as set forth above, but does not specifically teach wherein the proteins are mini-trap proteins.
Franklin teaches wherein the proteins are mini-trap proteins. Franklin states:
“The present disclosure describes the production of a modified version of aflibercept wherein the Fc portion is removed or absent and is referred to as aflibercept Mini Trap or VEGF MiniTrap.” (par [0028]).
Franklin further teaches:
“the Fc portion is enzymatically removed thus yielding MiniTrap.” (par [0029]).
Franklin expressly identifies this material as a “MiniTrap protein” and teaches forming it by cleaving full-length aflibercept (par [0038]). Franklin further teaches that:
“LC-MS analysis of this second capture flowthrough may demonstrate the presence of oxo-variants wherein one or more residues of MiniTrap are oxidized” (par 0038]).
Accordingly, Franklin teaches the claimed mini-trap protein and expressly teaches characterization of MiniTrap-containing samples by mass spectrometry.
Kim and Franklin contain functional similarities because both concern the analysis and characterization of proteins using mass spectrometry. Franklin specifically teaches MiniTrap proteins and teaches LC-MS analysis of samples comprising MiniTrap.
Therefore, at the time of the effective filing date, it would have been obvious to a person of ordinary skill in the art to modify the protein-analysis method, as taught by Kim, and incorporate analyzing a MiniTrap protein, as taught by Franklin, motivated to characterize MiniTrap proteins using mass spectrometry, as expressly contemplated by Franklin.
Claims 22-23 are rejected under 35 U.S.C. 103 as being unpatentable over Kim et al. (Analytical Chemistry, 2011) (Kim) in view of Ventouri et al. (Journal of Chromatography A, 2021) (Ventouri).
Regarding claim 22, Kim teaches the method of claim 1 as set forth above, including fractionating proteins by AF4 in an ammonium-salt buffer and sending a microflow of the fractionated sample to a mass spectrometer. Kim does not specifically teach that the ammonium salt is ammonium acetate or the concentrations recited in claims 22-23.
Ventouri teaches wherein the ammonium salt is ammonium acetate. Ventouri states:
“Various concentrations (25, 40, 80, 150 mM) of ammonium acetate (pH 6.9) were also investigated as … carrier-liquid solutions.” (pp. 2–3).
Accordingly, Ventouri expressly teaches ammonium acetate as the AF4 carrier-liquid salt, as required by claim 22.
Kim and Ventouri are analogous art because they are in the same field of endeavor of AF4 analysis and fractionation of proteins. Ventouri expressly evaluates AF4 of β-D-galactosidase using carrier liquids containing ammonium acetate and states that “[p]reservation of protein structural integrity during AF4 analysis was essential.” (abstract). Ventouri further explains that a significant aspect of its work was studying the effect of different AF4 carrier liquids and specifically investigated “the possibility of using an ammonium acetate carrier liquid.” (p. 4)
Therefore, at the time of the effective filing date, it would have been obvious to a person of ordinary skill in the art to modify the AF4 protein-analysis method, as taught by Kim, and incorporate ammonium acetate as the ammonium-salt carrier liquid, as taught by Ventouri, motivated to provide a known alternative carrier liquid for AF4 protein analysis and to investigate the effect of carrier-liquid composition and ionic strength on the analyzed proteins.
Regarding claim 23, Ventouri teaches the claimed ammonium-salt concentration. Ventouri expressly teaches:
“Various concentrations (25, 40, 80, 150 mM) of ammonium acetate (pH 6.9) were also investigated as … carrier-liquid solutions.” (p. 2-3).
In particular, Ventouri expressly teaches 150 mM ammonium acetate , which is expressly recited as one of the alternatives of claim 23 and also falls within the recited ranges including 25–500 mM, 50–450 mM, 75–400 mM, 100–350 mM, 100–300 mM, 100–250 mM, 100–200 mM, 125–175 mM, 140–160 mM, 140–150 mM, 145–150 mM, and 145–155 mM.
Ventouri additionally reports AF4 experiments using 140 mM ammonium acetate as the carrier solution (p. 5), further confirming the use of concentrations within the claimed ranges.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to XIAOYUN R XU, Ph. D. whose telephone number is (571)270-5560. The examiner can normally be reached M-F 8am-5pm.
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/XIAOYUN R XU, Ph.D./ Primary Examiner, Art Unit 1797
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