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 .
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.
Claim Objections
Claim 46 is objected to because of the following informalities: Claim 46 recites in the wherein clause “the nanoparticle” should be – the nanoparticles – because element (a) recites at least two nanoparticles. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 49-50, 55 and 71-73 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 49 recites the limitation of “wherein the third of the at least two phases” lacks antecedent basis because claim 46 does not recite a third phase. Additionally, the claim is unclear whether the third of the at least two phases is an optional limitation or required limitation because claim 46 only requires two phases. Claim 50 is being rejected as being dependent from claim 49
Claims 55 and 71-73 recite the limitations of nanoparticles and microparticles. Therefore, the claims are unclear to whether the density is in nanoparticles or microparticles.
Claim Rejections - 35 USC § 102
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 46-69, 71-74 and 76-78 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Sule et al. (“Rapid Analysis of Antibody Self-Association in Complex Mixtures Using Immunogold Conjugates”, Mol. Pharmaceutics, vol. 10, pgs. 1322-1331, published 2013), hereinafter Sule II).
Sule II teaches identifying of monoclonal antibodies (mAbs) in the initial discovery process that not only have high binding affinity but also have high solubility and low viscosity would simplify the development of safe and effective antibody therapeutics (see abstract). Sule II further teaches in the abstract gold nanoparticles are coated with polyclonal antibodies specific for human antibodies, and then human mAbs are captured from dilute antibody solutions. Sule II teaches antibody-gold conjugates were mixed with mAb solutions (50 µg/mL mAb) prepared at various solution conditions (pH 4.3-6.5, 0-300 mM NaC1) in a 384-wll transparent polystyrene plate and after 2 h, the absorbance spectra (400-700 nm) of the antibody-gold conjugates were measured (pg. 1324, left col., para. 2), which would read on buffered salt for soluble phase, see claims 47. Fig. 1 shows the overview of affinity-capture self-interaction nanoparticle spectroscopy wherein gold nanoparticles (20 nm) are coated with variable ratios of capture to non-capture antibodies, and then human monoclonal antibodies (mAbs) are adsorbed to generate conjugates with a range of mAb loading (also see caption), which would read on adherent phase, see claim 48 and the protein, the nanoparticle, and the buffered salt are combined to from a sample.
The limitation of “for making a low viscosity pharmaceutical formulation containing a protein having the potential to self-associate when it is at a high concentration” is directed to intended use. There must be a structural difference between the claimed mixture and the prior art reference’s solution to patentably distinguish the claimed mixture. Because Sule II’s solution reads on the claimed bioanalytical mixture, the solution would be capable of performing the intended use of the claim.
With respect to claim 47, Sule teaches antibody-gold conjugates were mixed with mAb solutions (50 µg/mL mAb) prepared at various solution conditions (pH 4.3-6.5, 0-300 mM NaC1) in a 384-wll transparent polystyrene plate and after 2 h, the absorbance spectra (400-700 nm) of the antibody-gold conjugates were measured (pg. 1324, left col., para. 2).
With respect to claim 48, Fig. 1 shows the overview of affinity-capture self-interaction nanoparticle spectroscopy wherein gold nanoparticles (20 nm) are coated with variable ratios of capture to non-capture antibodies, and then human monoclonal antibodies (mAbs) are adsorbed to generate conjugates with a range of mAb loading (also see caption).
With respect to claims 49-50, Fig. 1 shows aggregation phase from the self-associated protein and adhered to the surface of a nanoparticle.
With respect to claim 51, Sule II teaches gold nanoparticles are coated with polyclonal antibodies specific for human antibodies, and then human mAbs are captured from dilute antibody solutions (see abstract).
With respect to claims 52-53, Fig. 1 teaches gold nanoparticles are 20 nm (see caption).
With respect to claim 54, Fig. 1 shows the proteins are saturated with the gold nanoparticles.
With respect to claim 55, Sule II teaches 8.4 x1011 gold particles/mL (Fig. 2, caption), which would read on about 7x1011 particles/mL.
With respect to claim 56, Sule II teaches low mAb concentrations 5-50 µg/mL (see abstract).
With respect to claims 57-59, Fig. 1 shows the IgG antibody are conjugated to the gold nanoparticles.
With respect to claim 60, Sule II teaches monoclonal antibody (see abstract).
With respect to claims 61-63, Sule II teaches antibody-gold conjugates were mixed with mAb solutions (50 µg/mL mAb) prepared at various solution conditions (pH 4.3-6.5, 0-300 mM NaC1) (pg. 1324, left col., para. 2).
With respect to claim 64, Sule II teaches low mAb concentrations 5-50 µg/mL (see abstract).
With respect to claim 65, the recitation of “is excited with a light” is directed to intended use. There must be a structural difference between the claimed mixture and the prior art reference’s solution to patentably distinguish the claimed mixture. Because Sule II’s solution reads on the claimed bioanalytical mixture, the solution would be capable of performing the intended use of the claim. Additionally, Sule II does teach nanoparticle spectroscopy (see abstract).
With respect to claim 66, the recitation of “is measured at multiple wavelengths ranging from 450 nm to about 750 nm” is directed to intended use. There must be a structural difference between the claimed mixture and the prior art reference’s solution to patentably distinguish the claimed mixture. Because Sule II’s solution reads on the claimed bioanalytical mixture, the solution would be capable of performing the intended use of the claim.
With respect to claims 67-69, these recited results are directed to the intended use of claim 66. There must be a structural difference between the claimed mixture and the prior art reference’s solution to patentably distinguish the claimed mixture. Because Sule II’s solution reads on the claimed bioanalytical mixture, the solution would be capable of performing the intended use of the claim.
With respect to claims 71-73, Sule II teaches 4.67x1011 particles/mL (pg. 1323, right col., para. 1) and Sule II teaches 8.4x1011 gold particles/mL (Fig. 2, caption). Thus, these values would read on about 6.3x1011 particles/mL and about 8x1011 particles/mL.
With respect to claim 74, Fig. 2 teaches 150 mM NaCl (see caption).
With respect to claim 76, Sule II teaches 95% of supernatant was removed and the conjugates were resuspended in the remaining 5% of the pelleted solution (see pg. 1323, left col., para. 1 and Fig. 1). Note that the recitation of “in excess of a minimum concentration necessary to completely cover the nanoparticles” is directed to product-by-process, as the claimed protein is in at least two phases. Fig. 1 shows antibodies completely cover the nanoparticles.
With respect to claim 77, Sule II teaches evaluating the phase behavior of each mAb at high antibody concentration 50mg/mL (see pg. 1327, left col., middle of para. 1). Meanwhile, the recitation of “wherein the protein is at a high concentration when it is present at a concentration” is optional. Because the prior art’s solution has all the structural limitations of the claimed mixture, the protein is capable of being at high concentration.
With respect to claim 78, Sule II teaches gold nanoparticles are coated with polyclonal antibodies specific for human antibodies, and then human mAbs are captured from dilute antibody solutions (see abstract). Sule II teaches antibody-gold conjugates were mixed with mAb solutions (50 µg/mL mAb) prepared at various solution conditions (pH 4.3-6.5, 0-300 mM NaC1) in a 384-wll transparent polystyrene plate and after 2 h, the absorbance spectra (400-700 nm) of the antibody-gold conjugates were measured (pg. 1324, left col., para. 2). Fig. 1 shows the overview of affinity-capture self-interaction nanoparticle spectroscopy wherein gold nanoparticles (20 nm) are coated with variable ratios of capture to non-capture antibodies, and then human monoclonal antibodies (mAbs) are adsorbed to generate conjugates with a range of mAb loading (also see caption). Sule II teaches 8.4 x1011 gold particles/mL (Fig. 2, caption), which would read on about 8x1011 particles/mL. Fig. 2 teaches 150 mM NaCl (see caption). Sule II teaches evaluating the phase behavior of each mAb at high antibody concentration 50mg/mL (see pg. 1327, left col., middle of para. 1). Meanwhile, the recitation of “when it is present in a formulation” is intended use. Because the prior art’s solution has all the structural limitations of the claimed mixture, the solution is capable of performing the intended use.
Claims 46-54, 56-69, 74, and 76-77 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Sule et al. (“High-Throughput Analysis of Concentration-Dependent Antibody Self-Association”, Biophysical Journal, volume 101, October 2011, pgs. 1749-1757, published 2011, hereinafter Sule).
Sule teaches a nanoparticle-based method, termed self-interaction nanoparticle spectroscopy, that is capable of rapidly measuring concentration-dependent self-interactions for three human monoclonal antibodies with unique solution behaviors and the findings will guide rational manipulation of antibody phase behavior (see abstract). Sule teaches using antibody-gold conjugates to characterize antibody self-association, we first sought to immobilize two mAbs (mAb1 and mAb2) on 20 nm gold nanoparticles in a manner that would result in a near-monolayer coverage (see pg. 1751, left col., para. 1 of Results). Sule further teaches a range of pH and ionic strength values to identify conditions that would lead to antibody immobilization for both wild-type and thiolated antibodies while promoting high colloidal stability of the conjugate (see pg. 1751, left col., middle of para. 1 of Results), which would read on adherent phase, see claim 48. Sule teaches modified antibodies were then buffer exchange into acetate buffer (20 mM potassium acetate, pH 4.3) (see pg. 1750, right col., para. 1 of Methods), which would read on soluble phase, see claim 47. Sule teaches the plasmon wavelength for mAb2 conjugates at pH 6 is lower at 150 mM NaCl than at 50 mM NaC1 (see pg. 1750, left col., para. 1 of Comparison of SINS and light-scattering measurements), which would read on a buffered salt and wherein the protein, the nanoparticle, and the buffered salt are combined to form a sample.
The limitation of “for making a low viscosity pharmaceutical formulation containing a protein having the potential to self-associate when it is at a high concentration” is directed to intended use. There must be a structural difference between the claimed mixture and the prior art reference’s solution to patentably distinguish the claimed mixture. Because Sule’s solution reads on the claimed bioanalytical mixture, the solution would be capable of performing the intended use of the claim.
With respect to claim 47, Sule teaches modified antibodies were then buffer exchange into acetate buffer (20 mM potassium acetate, pH 4.3) (see pg. 1750, right col., para. 1 of Methods). Sule teaches the plasmon wavelength for mAb2 conjugates at pH 6 is lower at 150 mM NaCl than at 50 mM NaC1 (see pg. 1750, left col., para. 1 of Comparison of SINS and light-scattering measurements).
With respect to claims 48-49, Sule teaches using antibody-gold conjugates to characterize antibody self-association, we first sought to immobilize two mAbs (mAb1 and mAb2) on 20 nm gold nanoparticles in a manner that would result in a near-monolayer coverage (see pg. 1751, left col., para. 1 of Results). Note that Sule’s antibodies read on the claimed protein, which would self associate to form an aggregate.
With respect to claim 50, Sule teaches the wild-type antibody is directly absorbed and the other in which primary amines on the antibody surface are converted to thiol moieties to facilitate immobilization (see pg. 1751, left col., para. 1 of Results).
With respect to claims 51-53, Sule teaches using antibody-gold conjugates to characterize antibody self-association, we first sought to immobilize two mAbs (mAb1 and mAb2) on 20 nm gold nanoparticles in a manner that would result in a near-monolayer coverage (see pg. 1751, left col., para. 1 of Results).
With respect to claim 54, Sule teaches the gold nanoparticles conjugate with antibodies at low protein concentrations (<40 µg/mL) display self-association behavior (see abstract). Sule teaches using antibody-gold conjugates to characterize antibody self-association, we first sought to immobilize two mAbs (mAb1 and mAb2) on 20 nm gold nanoparticles in a manner that would result in a near-monolayer coverage (see pg. 1751, left col., para. 1 of Results). Sule teaches the wild-type antibody is directly absorbed and the other in which primary amines on the antibody surface are converted to thiol moieties to facilitate immobilization (see pg. 1751, left col., para. 1 of Results), which would saturate with protein on the gold nanoparticles.
With respect to claim 56, Sule teaches antibodies at varying concentrations (5-40 µg/mL) (see pg. 1750, right col., para. 4).
With respect to claims 57-60, Sule teaches the gold nanoparticles conjugate with monoclonal antibodies at low protein concentrations display self-association behavior (see abstract and Fig. 1A).
With respect to claims 61-63, Sule teaches modified antibodies were then buffer exchange into acetate buffer (20 mM potassium acetate, pH 4.3) (see pg. 1750, right col., para. 1 of Methods). Sule teaches the plasmon wavelength for mAb2 conjugates at pH 6 is lower at 150 mM NaCl than at 50 mM NaC1 (see pg. 1750, left col., para. 1 of Comparison of SINS and light-scattering measurements).
With respect to claim 64, Sule teaches the gold nanoparticles conjugate with antibodies at low protein concentrations (<40 µg/mL) display self-association behavior (see abstract).
With respect to claim 65, the recitation of “is excited with a light” is directed to intended use. There must be a structural difference between the claimed mixture and the prior art reference’s solution to patentably distinguish the claimed mixture. Because Sule’s solution reads on the claimed bioanalytical mixture, the solution would be capable of performing the intended use of the claim. Additionally, Sule does teach nanoparticle spectroscopy (see abstract).
With respect to claim 66, the recitation of “is measured at multiple wavelengths ranging from 450 nm to about 750 nm” is directed to intended use. There must be a structural difference between the claimed mixture and the prior art reference’s solution to patentably distinguish the claimed mixture. Because Sule’s solution reads on the claimed bioanalytical mixture, the solution would be capable of performing the intended use of the claim.
With respect to claims 67-69, these recited results are directed to the intended use of claim 66. There must be a structural difference between the claimed mixture and the prior art reference’s solution to patentably distinguish the claimed mixture. Because Sule’s solution reads on the claimed bioanalytical mixture, the solution would be capable of performing the intended use of the claim.
With respect to claim 74, Sule teaches the plasmon wavelength for mAb2 conjugates at pH 6 is lower at 150 mM NaCl than at 50 mM NaC1 (see pg. 1750, left col., para. 1 of Comparison of SINS and light-scattering measurements).
With respect to claim 76, Sule teaches the gold nanoparticles conjugate with antibodies to display self-association behavior (see Fig. 1). Note that the recitation of “in excess of a minimum concentration necessary to completely cover the nanoparticles” is directed to product-by-process, as the claimed protein is in at least two phases. As stated above, Sule teaches protein concentrations with gold at different wavelengths (Fig. 1A).
With respect to claim 77, the recitation of “wherein the protein is at a high concentration when it is present at a concentration” is optional. Because the prior art’s solution has all the structural limitations of the claimed mixture, the protein is capable of being at high concentration.
Claims 46-51, 54, 56-69, 74, and 76-77 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Jayaraman et al. (“Plasmonic Measurements of Monoclonal Antibody Self-Association Using Self-Interaction Nanoparticle Spectroscopy”, Biotechnology and Bioengineering, Vol. 111, No. 8, pgs. 1513-1520, August, 2014).
Jayaraman teaches one of the most significant challenges in developing therapeutic monoclonal antibodies is their unpredictable solubilities and viscosities at the high concentrations required for subcutaneous delivery and improved version of self-interaction nanoparticle spectroscopy capable of characterizing both repulsive and attractive self-interactions between diverse mAbs (see abstract). Jayaraman further teaches in the abstract that SINS is self-interactions between diverse mAbs immobilized on gold nanoparticles increase (repulsion) or decrease (attraction) interparticle distances, which shift the wavelength of maximum absorbance (plasmon wavelength) in opposite directions (also see Fig. 1). Jayaraman further teaches the plasmon wavelengths for mAb B-gold conjugates are reduced in the presence of 150 mM NaC1 (see pg.1516, left col., para. 2).
The limitation of “for making a low viscosity pharmaceutical formulation containing a protein having the potential to self-associate when it is at a high concentration” is directed to intended use. There must be a structural difference between the claimed mixture and the prior art reference’s solution to patentably distinguish the claimed mixture. Because Jayaraman’s solution reads on the claimed bioanalytical mixture, the solution would be capable of performing the intended use of the claim.
With respect to claims 47-50 and 54, Fig. 1 shows a soluble phase (protein interactions), an adherent phase, wherein the protein is adhered to the surface of each of the at least two nanoparticles, and aggregated phase of aggregated protein is adhered to the surface of the nanoparticles.
With respect to claim 51, Fig. 1 shows gold nanoparticles (see abstract).
With respect to claim 56, Jayaraman teaches final concentration of 64 µg/mL (see pg. 1515, right col., para. 2).
With respect to claims 57-60, Fig. 1 shows monoclonal antibody.
With respect to claims 61-63, Jayaraman teaches the plasmon wavelengths for mAb B-gold conjugates are reduced in the presence of 150 mM NaC1 (see pg.1516, left col., para. 2).
With respect to claim 64, Jayaraman teaches final concentration of 64 µg/mL (see pg. 1515, right col., para. 2).
With respect to claim 65, the recitation of “is excited with a light” is directed to intended use. There must be a structural difference between the claimed mixture and the prior art reference’s solution to patentably distinguish the claimed mixture. Because Jayaraman’s solution reads on the claimed bioanalytical mixture, the solution would be capable of performing the intended use of the claim.
With respect to claim 66, the recitation of “is measured at multiple wavelengths ranging from 450 nm to about 750 nm” is directed to intended use. There must be a structural difference between the claimed mixture and the prior art reference’s solution to patentably distinguish the claimed mixture. Because Jayaraman’s solution reads on the claimed bioanalytical mixture, the solution would be capable of performing the intended use of the claim.
With respect to claims 67-69, these recited results are directed to the intended use of claim 66. There must be a structural difference between the claimed mixture and the prior art reference’s solution to patentably distinguish the claimed mixture. Because Jayaraman’s solution reads on the claimed bioanalytical mixture, the solution would be capable of performing the intended use of the claim.
With respect to claim 74, Jayaraman teaches the plasmon wavelengths for mAb B-gold conjugates are reduced in the presence of 150 mM NaC1 (see pg.1516, left col., para. 2).
With respect to claim 76, note that the recitation of “in excess of a minimum concentration necessary to completely cover the nanoparticles” is directed to product-by-process, as the claimed protein is in at least two phases. Fig. 1 shows antibodies completely cover the nanoparticles.
With respect to claim 77, Jayaraman teaches 0.1 mg/mL mAb solution (see pg. 1518, right col., para 2). Meanwhile, the recitation of “wherein the protein is at a high concentration when it is present at a concentration” is optional. Because the prior art’s solution has all the structural limitations of the claimed mixture, the protein is capable of being at high concentration.
Claim Rejections - 35 USC § 103
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.
Claims 55 and 70-75 are rejected under 35 U.S.C. 103 as being unpatentable over Jayaraman et al. (“Plasmonic Measurements of Monoclonal Antibody Self-Association Using Self-Interaction Nanoparticle Spectroscopy”, Biotechnology and Bioengineering, Vol. 111, No. 8, pgs. 1513-1520, August, 2014), as applied to claim 46 above, and further in view of Soane et al. (US2016/0074515A1, published 03/17/2016).
Jayaraman teaches one of the most significant challenges in developing therapeutic monoclonal antibodies is their unpredictable solubilities and viscosities at the high concentrations required for subcutaneous delivery and improved version of self-interaction nanoparticle spectroscopy capable of characterizing both repulsive and attractive self-interactions between diverse mAbs (see abstract). Jayaraman further teaches in the abstract that SINS is self-interactions between diverse mAbs immobilized on gold nanoparticles increase (repulsion) or decrease (attraction) interparticle distances, which shift the wavelength of maximum absorbance (plasmon wavelength) in opposite directions (also see Fig. 1). Jayaraman further teaches the plasmon wavelengths for mAb B-gold conjugates are reduced in the presence of 150 mM NaC1 (see pg.1516, left col., para. 2). Jayaraman teaches future work will also focus on expanding the evaluation of SINS to a greater range of solution conditions (pH, ionic strength, and excipients), as well as comparing these measurements to additional light scattering results to further evaluate and it is important to compare SINS measurements to solution properties (e.g., viscosity, opalescence, and solubility) to evaluate the utility of SINS for optimizing concentrated antibody formulations (see pg.1519, right col., para. 3).
Jayaraman does not explicitly teach the claimed density (claims 55 and 71-73), a viscosity-reducing excipient (claim 70), wherein the viscosity-reducing excipient is p-aminobenzoic (claim 71).
With respect to the claimed density (claims 55 and 71-73), it has been settled to be no more than routine experimentation for one of ordinary skill in the art to discover an optimum ratio for a result-effective variable in maximizing the ratio of conjugation between gold nanoparticles and antibodies. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum of workable ranges by routine experimentation" Application of Aller, 220 F.2d 454, 456, 105 USPQ 233, 235-236 (C.C.P.A. 1955). "No invention is involved in discovering optimum ranges of a process by routine experimentation." Id. at 458, 105 USPQ at 236-237. The "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art.” In particular, Jayaraman teaches mAb-pAb mixture (0.8 mg/mL) and nine parts of gold nanoparticles (2.85 x 1012) (see pg. 1514, right col., para. 2). Therefore, it would have been obvious to the person of ordinary skill to discover the optimum ratio of gold nanoparticles to antibodies based on routinely optimization for an effective binding and aggregation.
Soane teaches formulations and methods for the production thereof that permit the delivery of concentrated protein solutions and the methods to yield a lower viscosity liquid formulation or a higher concentration of therapeutic proteins in the liquid formulation, as compared to traditional protein solutions (at abstract). Soane further teaches in concentrated protein solutions, these macromolecules may strongly interact and even shape and surface energy distribution and “Hot-spots” for strong specific interactions lead to protein clustering increasing solution viscosity and to address these concerns, a number of excipient compounds are used in biotherapeutic formulations, aiming to reduce solution viscosity by impeding localized interactions and clustering (see para. [0009]). Soane teaches there is an additional need to achieve viscosity reduction while preserving the activity of the protein (see paras. [0010]-[0011]). Soane further teaches excipient compounds as disclosed herein can suppress protein clustering due to specific interactions between the excipient compound and the target protein in solution (see para. [0018]). Soane teaches the concentration of protein in the experimental solutions was determined by measuring the absorbance of the protein solution at a wavelength of 280nm in a UV/VIS spectrometer (see para. [0076] and Example 3). Soane further teaches therapeutic formulation contains at least 200 mg/mL of protein active ingredient (see paras. [0033] and [0057]).
Soane teaches high concentration solutions of therapeutic can be formulated with anionic aromatic small molecule compounds as excipient because the anionic aromatic excipient compound is thought to be a bulky, sterically hindered molecule that can associate with cationic segments of a protein and that they can shield these sections of the protein, thereby decreasing the interactions between protein molecules that render the protein-containing formulation viscous (at para. [0057]). Soane further teaches anionic aromatic excipient compounds may be para-aminobenzoic (at para. [0058]).
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to have used the self-interaction nanoparticle spectroscopy of Jayaraman with a viscosity-reducing excipient of Soane because Jayaraman teaches expanding the evaluation of self-interaction nanoparticle spectroscopy (SINS) to a greater range of solution conditions with excipients and Soane teaches excipient compounds are used to address the concerns of strong protein interactions (in concentrated proteins) that lead to protein clustering increasing solution viscosity. Thus, the person would have added viscosity-reducing excipient into the self-interaction nanoparticle spectroscopy solutions of biotherapeutic formulations to reduce solution viscosity by impeding localized interactions and clustering while preserving protein therapeutic ability.
The person would have a reasonable expectation of success incorporating the self-interaction nanoparticle spectroscopy with the excipient because it has been understood by Jayaraman and Soane to add excipients in biotherapeutic formulations.
With respect to claim 75, Soane does not exemplify para-aminobenzoic acid in the Examples. However, it would have been obvious to the person to have used the anionic para-aminobenzoic (p-aminobenzoic) of Soane because Soane teaches a finite number of anionic aromatic compounds as the viscosity-reducing excipient and the anionic aromatic excipient compounds are a bulky and sterically hindered molecules that can associate with cationic segments of a protein, which is able to shield these sections of the protein, thereby decreasing the interactions between protein molecules that render the protein-containing formulation viscous.
The person would have a reasonable expectation of success in using p-aminobenzoic because Soane discloses p-aminobenzoic as excipient in reducing viscosity and interactions between proteins.
Conclusion
No claim is allowed.
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/N.P.N/Examiner, Art Unit 1678
/SHAFIQUL HAQ/Primary Examiner, Art Unit 1678
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