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 .
Election/Restrictions
Applicant’s election with traverse of species: Protein digest and Chromatographic separation parameters in the reply filed on 16 January, 2026 is acknowledged.
The traversal is on the following grounds: (I) The species identified by the Restriction Requirement are all directed to the same category of invention, and (II) The Restriction Requirement has not identified any further reasons for a lack of unity; rather the international searching authority found that the unity requirement was satisfied. Applicants’ argument have been fully considered, but are not found persuasive because the test for distinct inventions is whether the product as claimed can be used in a materially different process. Furthermore, the product and method claims raise different and complex issues under 35 U.S.C. 112 and 101.
Group I (Protein digest) and Group II (Chromatographic separation parameters) lack unity of invention because even though the inventions of these groups require the technical feature of antigen binding protein, this technical feature is not a special technical feature as it does not make a contribution over the prior art in view of US 2005/0161399. US 2005/0161399 teaches reversed-phase liquid chromatography/mass spectrometry method of analysis of high molecular weight proteins including antibodies. Claims 6, 7, 10, 15, 16, 19, 24, 27-36 and 38-42 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim.
Elected species protein digest with trypsin endopeptidase and chromatographic separation parameters as specified in example 5 were searched. These species are not free of the prior art, also is subject to a non-statutory double patenting rejection.
The search was extended and prior art was found, which is included in the scope of claims 1-5, 8, 9, 11-14, 17, 18, 20-23, 25, 26, and 37. The search was not extended further in accordance with MPEP § 803.02.Priority
The present application filed 05/03/2023 is a 371 of PCT/US2021/57519 filed 11/01/2021 which claims benefit of US Provisional Patent Application 63/110,087 filed 11/05/2020. The benefit is acknowledged and the claims examined herein are treated as having an effective filling date of 11/05/2020.
Status of Claims/Application
The preliminary amendment of 05/03/2023 is acknowledged. Claims 2, 4, 5, 8, 12, 13, 14, 17, 18, 20-23, and 37 are amended, claims 6, 7, 10, 15, 16, 19, 24, 27-36 and 38-42 are cancelled. Claims 1-5, 8, 9, 11-14, 17, 18, 20-23, 25, 26, and 37 are currently pending and are examined on the merits herein.
Information Disclosure Statement
The Information Disclosure Statement(s) filed 05/03/2023 are acknowledged and have been considered.
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.
Claims 1, 18, 20, and 21 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by US 2005/0161399, published July 28, 2005.
US 2005/0161399 teaches a method for analyzing an antibody or a fragment comprising: (a) preparing an antibody or fragment for loading onto a reversed-phase chromatography column; (b) separating the antibody or fragment by reversed-phase chromatography using column, where the eluate from the reversed-phase chromatography is introduced into a device in-line with the reversed-phase chromatography column that determines the presence of the antibody or antibody fragment and (c) detecting the presence of antibody or fragment where the mobile phase of reversed-phase chromatography column comprises a water miscible organic solvent (Claim 16). US 2005/0161399 discloses that the antibody derived fragments may be derived through proteolytic cleavage or chemical cleavage [0023]. Their invention is directed to a method for analyzing an antibody or a fragment, comprising preparing a sample comprising the antibody or fragment for loading onto a high- performance liquid chromatography (HPLC) column; separating the antibody or fragment from the sample by reversed-phase HPLC on the column, where the eluate from the reversed-phase HPLC [0025]. US 2005/0161399 discloses that the gradient is established comprising introducing a mixture of a first solvent A and a second solvent B as the mobile phase for chromatographic separation, where first solvent A comprises a mixture at pH 2.0 of water and trifluoracetic acid (TFA) and said second solvent B comprises a mixture at pH 2.0 of 70% isopropanol, 20% acetonitrile 9.9% water and 0.1% TFA (See ¶ [0174]). Further teaches the solvents useful in the mobile phase of the present invention include alcohols selected from the group consisting of n-propanol, isopropanol, n-butanol and isobutanol (See ¶ [0016]). The mobile phase comprises a gradient of isopropanol from 5% propanol to 90% propanol (Claim 10). In other embodiments, the mobile phase comprises a gradient of isopropanol from 10% isopropanol to 60% isopropanol (See ¶ [0021]). In particularly preferred embodiments, the solvent is present at 25% of the mobile phase (See ¶ [0074]).
Regarding claim 18, US 2005/0161399 teaches protein fragments as used are fragments of a large protein created by cleaving the protein using limited proteolysis with an enzyme or chemical cleavage by reducing the disulfide bonds. For example, an IgG1 antibody can be effectively cleaved by Lys-C protease to generate Fc domain (50 kDa) and two Fab domains (50 kDa each) over a short time period below 1 hour. An IgG2 antibody can be cleaved with pepsin protease to generate Fc domain (50 kDa) and (Fab).sub.2 domain (100 kDa). An IgG1 or IgG2 antibody can be reduced to produce two light chains (25 kDa each) and two heavy chains (50 kDa each). These examples illustrate that the above methods produce antibody fragments, which are, in general, larger than 20 kDa. In contrast to fragments, peptides are products of enzymatic cleavage of proteins into peptides with typical sizes from 0.5 kDa to 5 kDa (See ¶ [0050]). RP-HPLC is able to separate polypeptides of nearly identical sequences, not only for small peptides such as those obtained through trypsin digestion, but even also for proteins as large as 5,300 Da(See ¶ [0055]). The N-terminal (variable) domains of both HCs and LCs contain variable CDRs. These variable CDR domains determine the specificity of interaction of the immunoglobulin with the antigen ([0126], page 15, col 2 and FIG 12). The selectivity of separation of the antibody variants was increased after the antibody was reduced and alkylated to generate two components: 24 kDa LC and 50 kDa HC (See ¶ [0136], Example 5). US 2005/0161399 discloses high molecular weight protein has a molecular mass of about 90 kDa (Claim 11). US 2005/0161399 further discloses high molecular weight protein has been cleaved to protein fragments having a molecular mass of 80 kDa (Claim 12).
Regarding claim 20, US 2005/0161399 teaches the method of determining the presence of the antibody or antibody fragment is a mass spectrometer positioned in-line with reversed-phase chromatography column such that the eluate from the reversed-phase column is introduced into the ion source of said mass spectrometer, and where mass spectrometer provides mass fragmentation data for the antibody or antibody fragments (Claim 17).
Regarding claim 21, US 2005/0161399 teaches the methods of the invention are particularly useful in determining the integrity of an antibody and in particular a therapeutic antibody (See ¶ [0115]).
All the above teachings are satisfying all of the limitations of claim 1, 18, 20, and 21.
Therefore, the disclosures of US 2005/0161399 anticipate the claimed invention.
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 2, 5, 23, and 26 are rejected under 35 U.S.C. 103 as being unpatentable over US 2005/0161399 (published July 28, 2005) in view of Rock et al. (“CDR3 length in antigen-specific immune receptors”, Journal of Experimental Medicine, 179(1), January 1, 1994, pp. 323–328).
US 2005/0161399 teaches the methods of analysis of portions of an antibody, such as e.g., an Fab, Fc, heavy chain (HC) and light chain (LC) regions of an antibody or combinations. The antibody derived fragments may be derived through proteolytic cleavage or chemical cleavage (See ¶ [0023]). The antibody fragments are four fragments (two light chains (25 kDa each) and two heavy chains (50 kDa each)) produced by reduction or alternatively or are fragments (Fc (50 kDa), and Fab(50 kDa)) produced by limited proteolysis (See ¶ [0049]).
US 2005/0161399 further teaches that the therapeutic function of antibodies is achieved through complementarity defining regions (CDRs) located in the variable region of heavy chain and variable region of light chain. The amino acid sequence of CDRs is chosen such a way as to give the antibody a strong affinity towards a target and block the development of a disease (See ¶ [0124], Example 4).
US 2005/0161399 do not teach about the specific complementarity determining region3 (CDR3) of a variable region of the antigen binding protein that comprise heavy chain (HCDR3) and/or light chain (LCDR3).
Rock et al. teach CDR3 loops are often critical for antigen binding in Igs (immunoglobulins) and appear to provide the principal peptide binding residues in TCRs (T cell receptors) (abstract). Structural analysis of antibody-antigen complexes shows that one or both of the CDR3 loops of Ig H and L chains are always involved in antigen contact (paragraph 1, page 323). Rock et al disclose gamma and delta chain CDR3s are more like those of Ig than alpha/beta TCR in both the disparity between heterologous chains of average CDR3 lengths and the pronounced variability of H and delta chain lengths. This suggests that gamma/delta TCRs as a group may recognize antigens in a manner akin to Ig (paragraph 4, page 326).
At the time before the effective filing date of the claimed invention , it would have been prima facie obvious to one of ordinary skill in the art to utilize the protein characterization method taught by US 2005/0161399 to isolate the antigen-antibody binding specific fragments of the complementarity determining region taught by Rock et al. to arrive at the presently claimed invention. The artisan of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success in enhancing drug efficacy through antigen-antibody mediated binding properties of proteins. It is prima facie obvious to substitute equivalents known in the art for the same purpose. MPEP §2144.06.
Regarding claims 2, 5, and 26, 2005/0161399 teach the immunoglobulin molecule consists of two heavy chains (HCs) and two light chains (LCs). The N-terminal (variable) domains of both HCs and LCs contain variable CDRs. These variable CDR domains determine the specificity of interaction of the immunoglobulin with the antigen and are referred to as the VH and VL domains, respectively, for the HC and the LC (See ¶ [0126]).
Regarding claim 23, Rock et al. analyses do indicate that gamma/beta TCRs are much more similar in their CDR3 lengths to Ig (paragraph 3, page 323).
Therefore, the presently claimed invention was prima facie obvious to one of ordinary skill in the art at the time of the effective filing date.
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over US 2005/0161399 (published July 28, 2005) in view of Dillon et al. (“Optimization of a reversed-phase high-performance liquid chromatography/mass spectrometry method for characterizing recombinant antibody heterogeneity and stability”, Journal of Chromatography A, 1120, January 30, 2006, pp. 112–120, filed with IDS dated 05/03/2023).
US 2005/0161399 teaches one LC is connected to one HC at the hinge region by a single disulfide bond. Two HCs are connected together by two disulfide bonds closely positioned in the hinge region between domains CH1 and CH2. In IgG2, one LC is connected to one HC between CH2 and CH2 region by a single disulfide bond. Two HCs are connected together by four disulfide bonds closely positioned in the hinge region between domains CH1 and CH2 (See ¶ [0126], FIG. 12). They proposed that the following modifications may be responsible for the heterogeneity: 1) deamidation of asparagine residue into aspartic acid residue (+1 Da); 2) isomerization of aspartic acid residue into isoaspartic acid residue (0 Da); 3) a reduced disulfide bond (+2 Da); 4) disulfide re-arrangement within the cysteine residues at the hinge region of IgG2 (disulfide bond scrambling). Their approach to resolve the disulfide arrangement includes labeling of free cysteine residues at low pH, peptide map of non-reduced protein followed by reduction. This peptide mapping approach involves laborious sample preparation and data interpretation procedures and may introduce artificial disulfide scrambling. The reversed-phase HPLC/MS analyses of intact antibodies presented herein does not require any sample preparation, it is quick and the data are easy to interpret and readily provides a method of monitoring disulfide re-arrangement at the hinge region of IgG2 using RP HPLC/MS of intact antibodies (See ¶ [0130]). US 2005/0161399 teaches RP-HPLC/MS has been used to identify the structure of the antibodies eluted from the HPLC, the elution can be used to monitor disulfide re-arrangement at the hinge region of IgG2 (See ¶[0131]).
US 2005/0161399 do not teach the structural mapping of the characterized protein fragments/peptides.
Dillon et al. teaches peptide mapping of collected RP fractions was also used to confirm that no significant differences in chemical modifications were present (3.1. Reversed-phase method development, paragraph 7, page 115). Dillon et al. also teach the protein in the collected fraction has remained soluble, it can then be digested for peptide mapping and/or directly infused into a mass analyzer (4.2. Identification of a unique terminal ladder amino acid sequence, page 118). Dillon et al. further teaches peptide mapping will continue to be a standard method for non-routine antibody analysis, this novel method requires minimal sample preparation and data analysis to determine the molecular weight by deconvolution of electrospray mass spectra (Discussion, paragraph 1, page 118).
At the time before the effective filing date of the claimed invention , it would have been prima facie obvious to one of ordinary skill in the art to utilize the protein characterization method taught by US 2005/0161399 along with implementation of protein structural mapping approach taught by Dillon et al. to arrive at the presently claimed invention. The artisan of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success with advanced characterization methods and testing assays with topographical and domain information of proteins in biopharmaceutical research. It is prima facie obvious to substitute equivalents known in the art for the same purpose. MPEP §2144.06.
Therefore, the presently claimed invention was prima facie obvious to one of ordinary skill in the art at the time of the effective filing date.
Claims 4, 8, 9, and 25 are rejected under 35 U.S.C. 103 as being unpatentable over US 2005/0161399 (published July 28, 2005) in view of Dillon et al. (“Development of an analytical reversed-phase high-performance liquid chromatography–electrospray ionization mass spectrometry method for characterization of recombinant antibodies”, Journal of Chromatography A, 1053, September 17, 2004, pp. 299–305,).
US 2005/0161399 teaches the gradient is established comprising introducing a mixture of a first solvent A and a second solvent B as the mobile phase for said HPLC, where the first solvent A comprises a mixture at pH 2.0 of water and trifluoracetic acid (TFA) and the second solvent B comprises a mixture at pH 2.0 of 70% isopropanol, 20% acetonitrile 9.9% water and 0.1% TFA (See ¶[0022]). In the instant claims, the use of TFA as a polar solvent in RP-HPLC for better resolution of peptides and proteins and due to its high polarity, it elutes early in chromatography. Thus the mixture of solvent A constitutes a polar mobile phase solvent.
US 2005/0161399 do not teach the use of 0.05% - 0.09% of TFA as the mobile phase B solvent in RP-HPLC.
Dillon et al. teaches 0.09% TFA and 90% acetonitrile for mobile phase B. A lower
level of TFA (0.01–0.05%) is preferred when coupled with online mass spectral analysis in order to minimize ion suppression during the electrospray process with a minimal loss
in resolution capabilities (3.1. Method development, paragraph 6, page 302). Dillon et al disclose that in order to increase the MS signal intensity, the percentage of the acids
was decreased to 0.05% TFA (3.2 Applications, paragraph 1, page 303).
At the time before the effective filing date of the claimed invention , it would have been prima facie obvious to one of ordinary skill in the art to utilize the protein characterization method taught by US 2005/0161399 along with optimization mobile phase for characterizing monoclonal antibody taught by Dillon et al. to arrive at the presently claimed invention. The artisan of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success with improved chromatography and better resolution of antibody fragment variants. It is prima facie obvious to substitute equivalents known in the art for the same purpose. MPEP §2144.06.
Therefore, the presently claimed invention was prima facie obvious to one of ordinary skill in the art at the time of the effective filing date.
Claims 11-13, 14, 17, and 37 are rejected under 35 U.S.C. 103 as being unpatentable over US 2005/0161399 (published July 28, 2005) in view of Dillon et al. (“Development of an analytical reversed-phase high-performance liquid chromatography–electrospray ionization mass spectrometry method for characterization of recombinant antibodies”, Journal of Chromatography A, 1053, September 17, 2004, pp. 299–305).
US 2005/0161399 teaches about the using C8 or C18 stationary phase that has been modified such that the radius of curvature inside the pore (120 angstroms) approached the size of the protein molecule being analyzed. In certain embodiments, methods of the invention are employed for the analysis of antibodies. It is contemplated that in such embodiments employing a stationary phase having a pore size of from about 150 .ANG. to about 350 .ANG. may be particularly useful (See ¶ [0067]). US 2005/0161399 discloses commonly used materials are dextran, cellulose, agarose and copolymers of styrene and vinylbenzene in which the divinylbenzene both cross-links the polystyrene strands and contains the charged groups. Table 2 gives the composition of many ion exchangers (See ¶ [0088]). In the instant claim, divinylbenzene resin column (AGILENT) are used which has a standard pore size between 3um-10um.
US 2005/0161399 further teaches that the porosity of the matrix is an important feature because the charged groups are both inside and outside the matrix and because the matrix also acts as a molecular sieve. Large molecules may be unable to penetrate the pores; so the capacity will decease with increasing molecular dimensions. The porosity of the polystyrene-based resins is determined by the amount of cross-linking by the divinylbenzene (porosity decreases with increasing amounts of divinylbenzene) (See ¶ [0090]).
US 2005/0161399 do not teach about the particle size of the column matrix as set forth in claims 11, 13, and 37.
Also, US 2005/0161399 do not disclose the chromatography column height as set forth in claim 14
Dillon et al teaches the optimized methods employed a Zorbax SB300 C8 column (150mm × 4.6 mm, 3.5um particle size, 300 °A pore size) and a Polaris C8-ether column (150mm × 4.6 mm, 3.0um particle size, 200 °A pore size) (2.2 Reversed-phase HPLC, paragraph 1, page 301). Dillon et al. discloses using the Zorbax SB300 C8 column of 3.5um particle size and 300 °A pore size (3.1 Method Development, paragraph 3, page 302). Dillon et al. teaches the preferred columns were a Zorbax SB300 C8 column (150mm × 4.6 mm, 3.5um particle size, 300 °A pore size) and a Polaris C8-ether column (150mm × 4.6 mm, 3.0um particle size, 200 °A pore size) (3.1 Method Development, paragraph 6, page 302).
At the time before the effective filing date of the claimed invention , it would have been prima facie obvious to one of ordinary skill in the art to utilize the parameters of RP-HPLC for characterization of antibodies taught by US 2005/0161399 along with enhanced chromatographic column composition and height taught by Dillon et al. to arrive at the presently claimed invention. The artisan of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success with enhanced chromatographic separation efficiency, analysis time, and better resolution of antibody variants and hydrophobic proteins. It is prima facie obvious to substitute equivalents known in the art for the same purpose. MPEP §2144.06.
Therefore, the presently claimed invention was prima facie obvious to one of ordinary skill in the art at the time of the effective filing date.
Claim 22 is rejected under 35 U.S.C. 103 as being unpatentable over US 2005/0161399 (published July 28, 2005) in view of Dillon et al. (“Optimization of a reversed-phase high-performance liquid chromatography/mass spectrometry method for characterizing recombinant antibody heterogeneity and stability”, Journal of Chromatography A, 1120, January 30, 2006, pp. 112–120, filed with IDS dated 05/03/2023).
The teachings of US 2005/0161399 are discussed above. However, US 2005/0161399 do not specify the composition of the protein molecules/polypeptides consisting of antibody or antigen-binding fragment, derivative of an antibody or antibody fragment, or a fusion polypeptide.
Dillon et al. teach the reversed-phase method was required to improve the chromatography of these more hydrophobic antibodies and to resolve the variants and
degradants associated with antibody heterogeneity and stability (see Results, 1st paragraph). The ability to resolve the variants and degradants associated with antibody heterogeneity and stability was a critical factor in column selection (see Results; 3.1 Reversed-phase method development, 4th paragraph). Dillon et al. identified the fragment antigen-binding (Fab) portion of the IgG1 by the unique fragmentation pattern that was identified to be in a conserved region of the upper hinge. Respective peaks were identified as light chain, the N-terminal portion of the heavy chain above the hinge, and the IgG missing one of the Fab regions (see Results; 3.2 Pharmaceutical applications of the method, 2nd paragraph, Fig. 7). Dillon et al. teaches LC/MS analysis of antibodies represents a significant new tool to elucidate the structural basis of antibody heterogeneity and its possible implications on function (see Discussion, 4.4 Mechanism of enhanced chromatography, last paragraph).
At the time before the effective filing date of the claimed invention, it would have been prima facie obvious to one ordinary skill in the art to substitute the types of protein characterized by the method as taught by US 2005/0161399 with wider range of protein selection from the group consisting of an antibody or antigen-binding fragment, derivative of an antibody or antibody fragment, and a fusion polypeptide taught by Dillon et al. to arrive at the presently claimed invention. The artisan of ordinary skill would have been motivated to do so with a reasonable expectation of success because protein fragmentation followed by purification method can be utilized for more complex protein structures or other fusion proteins as taught by Dillon et al. It is prima facie obvious to substitute equivalents known in the art for the same purpose.
Therefore, the presently claimed invention was prima facie obvious to one of ordinary skill in the art at the time of the effective filing date.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 18, 20, and 21 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4 of U.S. Patent No. 7,329,353, issued February 12, 2008 as discussed above and in view of US 2005/0161399 (published July 28, 2005). Although the claims at issue are not identical, they are not patentably distinct from each other.
US’353 claims a method of determining the presence of an antibody degradation product in an antibody sample, with a method comprising: (a) performing RP-HPLC on said antibody sample under conditions (claim 1); where the mobile phase of the reversed-phase HPLC comprises a water miscible organic solvent having a C18 eluotropic strength coefficient of at least 6.0, and (b) determining the molecular weight data of the components of the antibody sample using ESI-MS (claim 1). US’353 discloses correlating the molecular weight data from the antibody sample to data obtained from known protein standards (claim 2) and the known protein standard is an antibody sample that has not undergone degradation (claim 3). US’353 further claims that product selected from the group consisting of a dimer, a cleavage product, oxidation of the antibody sample, deamidation of the antibody sample, N-terminal pyroglutamation of the antibody sample and disulfide bond scrambling of the antibody sample (claim 4).
The US’353 differ from the instant claims in that they do not claim that TFA was used.
The teachings of US 2005/0161399 are discussed above. US 2005/0161399 teaches that TFA satisfies requirements for RP-HPLC - the nonspecific interactions of the protein with the solid phase due to the negatively charged silanol groups on the solid phase are typically suppressed by maintaining low pH of the mobile phase and adding anionic pairing reagents to mask basic amino acid residues on the surface of protein (See ¶ [0075]).
At the time before the effective filing date of the claimed invention , it would have been prima facie obvious to one of ordinary skill in the art to utilize the parameters of RP-HPLC for characterization of antibodies taught by US’353 along with the preferred mobile phase solvent taught by US 2005/0161399 to arrive at the presently claimed invention. The artisan of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success with enhanced chromatographic separation efficiency, analysis time, and better resolution of antibody variants and hydrophobic proteins. It is prima facie obvious to substitute equivalents known in the art for the same purpose.
Claims 4, 8, 9, 11-13, 14, 17, 25, and 37 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4 of U.S. Patent No. 7,329,353, issued February 12, 2008 as discussed above and in view of Dillon et al. (“Development of an analytical reversed-phase high-performance liquid chromatography–electrospray ionization mass spectrometry method for characterization of recombinant antibodies”, Journal of Chromatography A, 1053, September 17, 2004, pp. 299–305).
The claims of US’353 are as discussed above.
The claims of US’353 differ from the instant claims in that they do not claim chromatography solvent conditions, column matrix composition and parameters.
The teachings of Dillon et al. are discussed above.
At the time before the effective filing date of the claimed invention , it would have been prima facie obvious to one of ordinary skill in the art to utilize the parameters of RP-HPLC for characterization of antibodies taught by US’353 along with enhanced chromatographic column composition and height taught by Dillon et al. to arrive at the presently claimed invention. The artisan of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success with enhanced chromatographic separation efficiency, analysis time, and better resolution of antibody variants and hydrophobic proteins. It is prima facie obvious to substitute equivalents known in the art for the same purpose.
Claims 2, 5, 23, and 26 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4 of U.S. Patent No. 7,329,353, issued February 12, 2008 as discussed above in view of Rock et al. (“CDR3 length in antigen-specific immune receptors”, Journal of Experimental Medicine, 179(1), January 1, 1994, pp. 323–328).
The claims of US’353 are as discussed above.
The claims of US’353 differ from the instant claims in that they do not teach about the specific complementarity determining region3 (CDR3) of a variable region of the antigen binding protein that comprise heavy chain (HCDR3) and/or light chain (LCDR3).
The teachings of Rock et al. are discussed above.
At the time before the effective filing date of the claimed invention , it would have been prima facie obvious to one of ordinary skill in the art to utilize the protein characterization method taught by US’353 to isolate the antigen-antibody binding specific fragments of the complementarity determining region taught by Rock et al. to arrive at the presently claimed invention. The artisan of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success in enhancing drug efficacy through antigen-antibody mediated binding properties of proteins. It is prima facie obvious to substitute equivalents known in the art for the same purpose.
Claims 3 and 22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4 of U.S. Patent No. 7,329,353, issued February 12, 2008 as discussed above in view of Dillon et al. (“Optimization of a reversed-phase high-performance liquid chromatography/mass spectrometry method for characterizing recombinant antibody heterogeneity and stability”, Journal of Chromatography A, 1120, January 30, 2006, pp. 112–120, filed with IDS dated 05/03/2023).
The claims of US’353 are as discussed above.
The claims of US’353 differ from the instant claims in that they do not teach the structural mapping of the characterized protein fragments/peptides nor specify the composition of the protein molecules/polypeptides consisting of antibody or antigen-binding fragment, derivative of an antibody or antibody fragment, or a fusion polypeptide.
The teachings of Dillon et al are as discussed above.
At the time before the effective filing date of the claimed invention, it would have been prima facie obvious to one ordinary skill in the art to substitute the types of protein characterized by the method as taught by US’353 with wider range of protein selection from the group consisting of an antibody or antigen-binding fragment, derivative of an antibody or antibody fragment, and a fusion polypeptide taught by Dillon et al. to arrive at the presently claimed invention. The artisan of ordinary skill would have been motivated to do so with a reasonable expectation of success because protein fragmentation followed by purification method can be utilized for more complex protein structures or other fusion proteins as taught by Dillon et al. It is prima facie obvious to substitute equivalents known in the art for the same purpose.
Conclusion
No claims are allowed.
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/KOYELI BANERJEE/Examiner, Art Unit 1658
/LIANKO G GARYU/Supervisory Patent Examiner, Art Unit 1654