DETAILED ACTION
In application filed on 06/03/2022, Claims 1-32 are pending. The claim set submitted on 11/21/2025 is considered because this is the most recent claim set with some preliminary amendments. Claims 1-8 and 21-32 are considered in the current office 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 .
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 11/18/2022, 01/11/2024, 01/11/2024, 07/26/2024, 10/01/2024, 05/20/2025, 05/20/2025 and 04/13/2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
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 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 and 4-8 are rejected under 35 U.S.C. 102 (a) (1) as being anticipated by Zhang et al. (US20120041172A1, Submitted in IDS of 11/18/2022).
Regarding Claim 1, Zhang teaches a method of purifying degarelix or a pharmaceutically acceptable salt thereof containing compound A (See Abstract, Para 0001…a method for the manufacture of synthetic peptides, in particular to the manufacture of the decapeptide degarelix; The claimed “or a pharmaceutically acceptable salt thereof containing compound A” is viewed as optional and thus not required by the claim), the method comprising:
(a) eluting the degarelix (See Para 0079… The product is eluted by 24% B+76% A, wherein the product is degarelix; the claimed “or a pharmaceutically acceptable salt thereof containing compound A” is interpreted as optional” ) through a chromatographic column (See Para 0079… a column (2.5 cm×34 cm) packed with reversed phase C-18 material) with a mobile phase (See Para 0079… 10% B+90% C for 2-3 column volumes followed by 90% A+10% B for 2-3 column volumes) to separate the degarelix or pharmaceutically acceptable salt thereof (See Para 0013…degarelix, Ac-D-2Nal-D-Phe(4Cl)-D-3 Pal-Ser-4Aph(Hor)-D-4Aph(Cbm)-Leu-ILys-Pro-D-Ala-NH2; the claimed “or a pharmaceutically acceptable salt thereof” is interpreted as optional” ) and the compound A (referred to as of Ac-D-2Nal-D-Phe(4Cl)-D-3 Pal-Ser-X-D-4Aph(Cbm)-Leu-ILys-Pro-D-Ala-NH2, wherein X is 4-([2-(5-hydantoyl)]-acetylamino)-phenylalanine [Para 0013]), to produce a purified form of degarelix or pharmaceutically acceptable salt (See Para 0079… the product (degarelix) is eluted using 50% buffer A+50% buffer B) thereof (See Para 0079… The solution of the purified product containing 50% ethanol is concentrated on a rotary evaporator; See Para 0079… 4-([2-(5-Hydantoyl)]acetylamino)-phenylalanine could not be detected in the product (HPLC), thereby teaching that compound A is not detected in the purified form of degarelix), and
(b) isolating the purified form of degarelix or pharmaceutically acceptable salt thereof containing Compound A (See Para 0079… Step 15…The product is purified using a two-step purification protocol… A total of 11.8 g (overall yield 37%) of degarelix is obtained as a fluffy solid, thereby teaching isolating the purified degarelix or pharmaceutically acceptable salt thereof),
wherein the eluting (See Para 0079… The product is eluted …) comprises isocratically eluting the degarelix or pharmaceutically acceptable salt thereof containing Compound A (See Para 0079… the product is applied to the column and purification performed by applying a step gradient starting with 10% B+90% C for 2-3 column volumes…; Examiner submits under BRI that “a step gradient” teaches “isocratically eluting”) from the chromatographic column (See Para 0079… A volume from the filtered solution from step 14 corresponding to 1.6 g of the product is applied to the column) with the mobile phase (See Para 0079…The product is eluted by 24% B+76% A).
Regarding Claim 4, Zhang further teach that the degarelix or pharmaceutically acceptable salt thereof containing Compound A (See Para 0079… The fractions containing product, thereby teaching “degarelix”) is applied to the chromatographic column as a solution (See Para 0079… The fractions containing product with the acceptable purity are pooled and desalted using the same column) comprising acetic acid in a concentration of 0.01-1% by volume (See Para 0079… Desalting is performed using buffer A (1% aqueous acetic acid), thereby teaching “0.01-1% by volume”).
Regarding Claim 5, Zhang further teaches that the purified degarelix or pharmaceutically acceptable salt thereof (See Para 0014… degarelix; the claimed “or a pharmaceutically acceptable salt thereof” is interpreted as optional”) comprises not more than 0.3 wt.% of compound A (referred to as of Ac-D-2Nal-D-Phe(4Cl)-D-3 Pal-Ser-X-D-4Aph(Cbm)-Leu-ILys-Pro-D-Ala-NH2, wherein X is 4-([2-(5-hydantoyl)]-acetylamino)-phenylalanine [Para 0013-0014]) relative to the degarelix or a pharmaceutically acceptable salt thereof (See Para 0014…degarelix prepared by the method of the invention comprising 0.3% by weight or less of Ac-D-2Nal-D-Phe(4Cl)-D-3 Pal-Ser-X-D-4Aph(Cbm)-Leu-ILys-Pro-D-Ala-NH2, wherein X is 4-([2-(5-hydantoyl)]-acetylamino)-phenylalanine, in particular 0.1% by weight or less, most particularly 0.01% by weight or less).
Regarding Claim 6, Zhang further teaches purified degarelix or a pharmaceutically acceptable salt thereof prepared (See Para 0079… the product (degarelix) is eluted using 50% buffer A+50% buffer B;…The solution of the purified product containing 50% ethanol is concentrated on a rotary evaporator; the claimed “or a pharmaceutically acceptable salt” is interpreted as optional) according to claim 1 (See Claim 1 rejection).
Regarding Claim 7, Zhang further teaches that the purified degarelix or pharmaceutically acceptable salt thereof according to claim 6 (See Claim 6 rejection…thereby teaching “the purified degarelix or pharmaceutically acceptable salt thereof”) comprises not more than 0.3 wt.% of compound A (referred to as of Ac-D-2Nal-D-Phe(4Cl)-D-3 Pal-Ser-X-D-4Aph(Cbm)-Leu-ILys-Pro-D-Ala-NH2, wherein X is 4-([2-(5-hydantoyl)]-acetylamino)-phenylalanine [Para 0013-0014]) relative to the degarelix or a pharmaceutically acceptable salt thereof (See Para 0014…degarelix prepared by the method of the invention comprising 0.3% by weight or less of Ac-D-2Nal-D-Phe(4Cl)-D-3 Pal-Ser-X-D-4Aph(Cbm)-Leu-ILys-Pro-D-Ala-NH2, wherein X is 4-([2-(5-hydantoyl)]-acetylamino)-phenylalanine, in particular 0.1% by weight or less, most particularly 0.01% by weight or less; the claimed “or a pharmaceutically acceptable salt thereof” is interpreted as optional”).
Regarding Claim 8, Zhang further teaches that a pharmaceutical composition (See Para 0010… pharmaceutically pure degarelix can be manufactured by solid phase synthesis using Fmoc as α-amino protecting group. “Pharmaceutically pure” indicates the product does not contain more than 0.3% by weight of any single impurity, where “pharmaceutically pure degarelix” teaches “pharmaceutical composition”) comprising the purified degarelix or pharmaceutically acceptable salt thereof of claim 6 (See Claim 6 rejection…thereby teaching “the purified degarelix or pharmaceutically acceptable salt thereof”; the claimed “or a pharmaceutically acceptable salt thereof” is interpreted as optional.)
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 2 is rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. (US20120041172A1, Submitted in IDS of 11/18/2022) as applied to claim 1 above, and further in view of Dasseux et al. (US20160324923A1).
Regarding Claim 2, Zhang further teaches that the chromatographic column (See Para 0079… a column (2.5 cm×34 cm) packed with reversed phase C-18 material) is a C18 resin (See Para 0079… a column (2.5 cm×34 cm) packed with reversed phase C-18 material).
Zhang does not explicitly teach the chromatographic column is an organo- silica grafted C18 resin having an average particle size of about 2 µm to about 20 µm and a pore size of about 100 Å to about 120 Å.
In the analogous art of peptides, compositions thereof, and methods for treating or preventing dyslipidemia, a cardiovascular disease, endothelial dysfunction, a macrovascular disorder, or a microvascular disorder, Dasseux teaches that the chromatographic column is an organo- silica grafted C18 resin having an average particle size of about 2 µm to about 20 µm and a pore size of about 100 Å to about 120 Å (See Para 0660… Purification of ApoA-I Mimics prepared according to Example 1 is performed by preparative reverse phase HPLC with a C18 stationary phase (grafted silica, 15 μm particle size, 120 Å pore size) using a water/acetonitrile gradient (with 0.1% TFA counter ion)).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Zhang to use the chromatographic column that is an organo- silica grafted C18 resin having an average particle size of about 2 µm to about 20 µm and a pore size of about 100 Å to about 120 Å., as taught by Dasseux for the benefit of purifying ApoA-I Mimics (Dasseux, Para 0659-0660), allowing for the development of additional peptides that can mimic the activity of ApoA-I in vivo, which are simple and cost-effective to produce. (Dasseux, Para 0008).
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. (US20120041172A1, Submitted in IDS of 11/18/2022) as applied to claim 1 above, and further in view of Ragnar-Tolf et al. (US20070264330A1) and further in view of Dadey et al. (US20100266655A1).
Regarding Claim 3, Zhang further teaches that the mobile phase (See Para 0079… 10% B+90% C for 2-3 column volumes followed by 90% A+10% B for 2-3 column volumes) comprises an ammonium acetate buffer solution (See Para 0079…buffer C (0.5 M aqueous ammonium acetate)) and acetonitrile (See Para 0080… c) Acetonitrile was used in purification instead of ethanol).
Zhang does not teach an ammonium acetate buffer solution having a pH of about 10.0 and a ratio of about 65: 35 (ammonium acetate buffer solution: acetonitrile).
In the analogous art of stable pharmaceutical formulations of pimavanserin, Ragnar-Tolf teaches an ammonium acetate buffer solution having a pH of about 10.0 and a ratio of ammonium acetate buffer solution: acetonitrile (See Para 0135…assay test was conducted using a Waters XTerra RP18 250×4.6 mm, 5 μm column maintained at 30° C. The mobile phase was acetonitrile-5 mM ammonium acetate at pH 10.0. Pimavanserin was detected by UV-absorption at 226 nm.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Zhang to incorporate a mobile phase having an ammonium acetate buffer solution having a pH of about 10.0 and a ratio of (solution (interpreted as an ammonium acetate buffer solution): acetonitrile), as taught by Ragnar-Tolf for the benefit of conducting as assay test of the Excipient Compatibility Study with Pimavanserin Tartrate Crystalline Form C, using a Waters XTerra RP18 250×4.6 mm, 5 μm column maintained at 30° C (Ragnar-Tolf, Para 0135), allowing for determination of pharmaceutically acceptable carriers, diluents, and/or excipients that when admixed with pimavanserin tartrate results in stable compositions having a long shelf life (Ragnar-Tolf, Para 0028).
The combination of Zhang and Ragnar-Tolf does not explicitly teach a mobile phase buffer having ammonium acetate buffer solution and acetonitrile in a ratio of about 65: 35.
In the analogous art of a risperidone sustained release delivery system for treatment of diseases ameliorated by risperidone compounds, which discloses reversed phase high performance liquid chromatography method for the quantization of risperidone and 9-hydroxy-risperidone, Dadey teaches a mobile phase buffer having ammonium acetate buffer solution and acetonitrile in a ratio of about 65 : 35 (See Para 0190-0191…The High Performance Liquid Chromatography had the following conditions: Mobile Phase: 35:65 acetonitrile : ammonium acetate).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Zhang and Ragnar-Tolf to incorporate that a mobile phase buffer having ammonium acetate buffer solution and acetonitrile in a ratio of about 65 : 35, as taught by Dadey for the benefit of conducting the reversed phase high performance liquid chromatography method for the quantization of risperidone and 9-hydroxy-risperidone (Dadey, Para 0190-0191), allowing for the development of sustained release formulations of risperidone that do not suffer from low bioavailability, poor release kinetics, injection site toxicity, relatively large volume injections, and inconveniently short duration of release (Dadey, Para 0008).
Claim 21 is rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. (US20120041172A1, Submitted in IDS of 11/18/2022) in view of Ragnar-Tolf et al. (US20070264330A1) and further in view of Dadey et al. (US20100266655A1) as applied to claim 3 above, and further in view of Barker et al. (US5384309A).
Regarding Claim 21, the method of claim 3 is obvious over Zhang in view of Ragnar-Tolf, further in view of Dadey
Zhang further teaches an ammonium acetate buffer solution (See Para 0079…buffer C (0.5 M aqueous ammonium acetate)).
Zhang does not teach 45mM ammonium acetate.
In the analogous art of peptide derivatives which are useful as inhibitors platelet function mediated by the GP llbllla receptor and for the prevention of thrombus formation, Barker teaches 45mM ammonium acetate (See Col. 21, lines 24-25…The desired title compound is eluted with 45 mM ammonium acetate at pH 7.3).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Zhang, Ragnar-Tolf and Dadey to incorporate 45mM ammonium acetate, as taught by Barker for the benefit of eluting the desired title compound (Barker, Col. 21, lines 24-25), allowing for the provision of inhibitors which, by blocking the the binding of fibrinogen (and/or related ligands such as fibronectin, vitronectin and von Willebrands factor) to the platelet GP llbllla receptor, antagonize the final common pathway of platelet aggregation and act as potent antithrombotics (Barker, Col. 1, lines 12-18).
Claim 22 is rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. (US20120041172A1, Submitted in IDS of 11/18/2022) as applied to claim 1 above, and further in view of Firestone et al. (US6613879B1).
Regarding Claim 22, Zhang further teaches that the mobile phase (See Para 0079…The product is eluted by 24% B+76% A) is performed at a flow rate of about 70 mL/min (See Para 0079…Purification is executed using a step gradient starting with 10% B for 2-3 column volumes, 29% B for 5-7 column volumes and a gradient from 29% B to 50% B over 3 column volumes at a flow rate of 70 ml/min.).
Zhang does not teach a flow rate of about 0.7 mL/min.
In the analogous art of a prodrug that is capable of being converted into a drug by the catalytic action of human fibroblast activation protein (FAPalpha), said prodrug having a cleavage site which is recognised by FAPalpha, and said drug being cytotoxic or cytostatic under physiological conditions, Firestone teaches a flow rate of about 0.7 mL/min (See Col. 28, lines 55-59… Separations were performed under isocratic conditions at a flow rate of 0.7 ml/min on a Nucleosil C-18 column, 100 mm longx4 mm I.D. with 5 μm particle size).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Zhang to incorporate a flow rate of about 0.7 mL/min, as taught by Firestone for the benefit of separating Free doxorubicin and doxorubicinpeptide conjugates (Firestone, Col. 28, lines 49-63), allowing for provision of methods and means for improving normal tissue tolerability of cytotoxic or cytostatic agents with known efficacy against a broad range of tumour tissues (Firestone, Col. 2, lines 55-59).
Claim 23 is rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. (US20120041172A1, Submitted in IDS of 11/18/2022) as applied to claim 4 above, and further in view of Chen et al. (US20180371022A1).
Regarding Claim 23, Zhang further teaches that the degarelix or pharmaceutically acceptable salt thereof containing compound A (See Para 0079… The fractions containing product, thereby teaching “degarelix”) is applied to the chromatographic column as a solution (See Para 0079… The fractions containing product with the acceptable purity are pooled and desalted using the same column) comprising acetic acid in a concentration of 1% by volume (See Para 0079… Desalting is performed using buffer A (1% aqueous acetic acid)).
Zhang does not teach “acetic acid in a concentration of 0.05-0.5% by volume”.
In the analogous art of a method of synthesizing linaclotide through completely selective formation of three disulfide bonds, Chen teaches “acetic acid in a concentration of 0.05-0.5% by volume” (See Para 0034…0.1 vol % aqueous acetic acid/acetonitrile is used as a mobile phase).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Zhang to incorporate “acetic acid in a concentration of 0.05-0.5% by volume”, as taught by Chen for the benefit of preparing linaclotide (Chen, Para 0034), allowing for the exploration of a linaclotide synthesis method which is performed under mild conditions, low in cost, high in yield, high in product purity, simple and stable in processes, and suitable for large-scale production (Chen, Para 0006).
Claim 24 is rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. (US20120041172A1, Submitted in IDS of 11/18/2022) as applied to claim 1 above.
Regarding Claim 24, Zhang further teaches that the degarelix or pharmaceutically acceptable salt thereof containing compound A (See Para 0079… The fractions containing product, thereby teaching “degarelix”) is applied to the chromatographic column as a solution (See Para 0079… The fractions containing product with the acceptable purity are pooled and desalted using the same column) comprising degarelix (See Para 0079… A total of 11.8 g (overall yield 37%) of degarelix is obtained as a fluffy solid, thereby teaching isolating the purified degarelix or pharmaceutically acceptable salt thereof).
While Zhang teaches the amount/yield of the obtained degarelix solution, Zhang does not explicitly teach the final concentration of the obtained degarelix solution.
MPEP § 2144.05, Part II, Subpart B holds that a particular parameter that is recognized as a result effective variable (“a variable that achieves a recognized result”) would be one, but not the only motivation for a person of ordinary skill in the art to experiment to reach another workable product or process. In the synthesis of synthetic peptides, the selection of optimal experimental conditions including final purification concentration of the peptides (products) could affect the dosage amounts towards pharmaceutical formulation. Thus, the final concentration of the obtained degarelix solution being at a concentration of about 0.01 mg/mL to about 10 mg/mL is a result effective variable.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to purify the obtained degarelix solution at a concentration of about 0.01 mg/mL to about 10 mg/mL for the benefit of providing degarelix at fractions containing product with the acceptable purity (Zhang, Para 0079), which allows for the provision of a method for the manufacture of degarelix, which is less costly than methods known in the art (Zhang, Para 0008).
Claims 25-26, 28, 30 and 32 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. (US20120041172A1, Submitted in IDS of 11/18/2022) in view of Ragnar-Tolf et al. (US20070264330A1), further in view of Dadey et al. (US20100266655A1) and further in view of Dasseux et al. (US20160324923A1).
Regarding Claim 25, Zhang teaches a method of purifying degarelix or a pharmaceutically acceptable salt thereof containing compound A (See Abstract, Para 0001…a method for the manufacture of synthetic peptides, in particular to the manufacture of the decapeptide degarelix; The claimed “or a pharmaceutically acceptable salt thereof containing compound A” is viewed as optional and thus not required by the claim), the method comprising:
(a) eluting the degarelix (See Para 0079… The product is eluted by 24% B+76% A, wherein the product is degarelix; the claimed “or a pharmaceutically acceptable salt thereof containing compound A” is interpreted as optional” ) through a chromatographic column (See Para 0079… a column (2.5 cm×34 cm) packed with reversed phase C-18 material) with a mobile phase (See Para 0079… 10% B+90% C for 2-3 column volumes followed by 90% A+10% B for 2-3 column volumes) to separate the degarelix or pharmaceutically acceptable salt thereof (See Para 0013…degarelix, Ac-D-2Nal-D-Phe(4Cl)-D-3 Pal-Ser-4Aph(Hor)-D-4Aph(Cbm)-Leu-ILys-Pro-D-Ala-NH2; the claimed “or a pharmaceutically acceptable salt thereof” is interpreted as optional” ) and the compound A (referred to as of Ac-D-2Nal-D-Phe(4Cl)-D-3 Pal-Ser-X-D-4Aph(Cbm)-Leu-ILys-Pro-D-Ala-NH2, wherein X is 4-([2-(5-hydantoyl)]-acetylamino)-phenylalanine [Para 0013]), to produce a purified form of degarelix or pharmaceutically acceptable salt (See Para 0079… the product (degarelix) is eluted using 50% buffer A+50% buffer B) thereof (See Para 0079… The solution of the purified product containing 50% ethanol is concentrated on a rotary evaporator; See Para 0079… 4-([2-(5-Hydantoyl)]acetylamino)-phenylalanine could not be detected in the product (HPLC), thereby teaching that compound A is not detected in the purified form of degarelix), and
(b) isolating the purified form of degarelix or pharmaceutically acceptable salt thereof containing Compound A (See Para 0079… Step 15…The product is purified using a two-step purification protocol… A total of 11.8 g (overall yield 37%) of degarelix is obtained as a fluffy solid, thereby teaching isolating the purified degarelix or pharmaceutically acceptable salt thereof),
wherein the eluting (See Para 0079… The product is eluted …) comprises isocratically eluting the degarelix or pharmaceutically acceptable salt thereof containing Compound A (See Para 0079… the product is applied to the column and purification performed by applying a step gradient starting with 10% B+90% C for 2-3 column volumes…, thereby teaching “isocratically eluting”) from the chromatographic column (See Para 0079… A volume from the filtered solution from step 14 corresponding to 1.6 g of the product is applied to the column) with the mobile phase (See Para 0079…The product is eluted by 24% B+76% A), wherein the mobile phase (See Para 0079… 10% B+90% C for 2-3 column volumes followed by 90% A+10% B for 2-3 column volumes) comprises an ammonium acetate buffer solution (See Para 0079…buffer C (0.5 M aqueous ammonium acetate)) and acetonitrile (See Para 0080… c) Acetonitrile was used in purification instead of ethanol), wherein the chromatographic column is a C18 resin (See Para 0079…a column (2.5 cm×34 cm) packed with reversed phase C-18 material).
Zhang does not teach an ammonium acetate buffer solution having a pH of about 10.0 and a ratio of about 65: 35 (ammonium acetate buffer solution: acetonitrile).
In the analogous art of stable pharmaceutical formulations of pimavanserin, Ragnar-Tolf teaches an ammonium acetate buffer solution having a pH of about 10.0 and a ratio of ammonium acetate buffer solution: acetonitrile (See Para 0135…assay test was conducted using a Waters XTerra RP18 250×4.6 mm, 5 μm column maintained at 30° C. The mobile phase was acetonitrile-5 mM ammonium acetate at pH 10.0. Pimavanserin was detected by UV-absorption at 226 nm.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Zhang to incorporate a mobile phase having an ammonium acetate buffer solution having a pH of about 10.0 and a ratio of (solution (interpreted as an ammonium acetate buffer solution): acetonitrile), as taught by Ragnar-Tolf for the benefit of conducting as assay test of the Excipient Compatibility Study with Pimavanserin Tartrate Crystalline Form C, using a Waters XTerra RP18 250×4.6 mm, 5 μm column maintained at 30° C (Ragnar-Tolf, Para 0135), allowing for determination of pharmaceutically acceptable carriers, diluents, and/or excipients that when admixed with pimavanserin tartrate results in stable compositions having a long shelf life (Ragnar-Tolf, Para 0028).
The combination of Zhang and Ragnar-Tolf does not explicitly teach a mobile phase buffer having ammonium acetate buffer solution and acetonitrile in a ratio of about 65: 35.
In the analogous art of a risperidone sustained release delivery system for treatment of diseases ameliorated by risperidone compounds, which discloses reversed phase high performance liquid chromatography method for the quantization of risperidone and 9-hydroxy-risperidone, Dadey teaches a mobile phase buffer having ammonium acetate buffer solution and acetonitrile in a ratio of about 65 : 35 (See Para 0190-0191…The High Performance Liquid Chromatography had the following conditions: Mobile Phase: 35:65 acetonitrile : ammonium acetate).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Zhang and Ragnar-Tolf to incorporate that a mobile phase buffer having ammonium acetate buffer solution and acetonitrile in a ratio of about 65 : 35, as taught by Dadey for the benefit of conducting the reversed phase high performance liquid chromatography method for the quantization of risperidone and 9-hydroxy-risperidone (Dadey, Para 0190-0191), allowing for the development of sustained release formulations of risperidone that do not suffer from low bioavailability, poor release kinetics, injection site toxicity, relatively large volume injections, and inconveniently short duration of release (Dadey, Para 0008).
The combination of Zhang, Ragnar-Tolf and Dadey does not teach wherein the chromatographic column is an organo-silica grafted C18 resin.
In the analogous art of peptides, compositions thereof, and methods for treating or preventing dyslipidemia, a cardiovascular disease, endothelial dysfunction, a macrovascular disorder, or a microvascular disorder, Dasseux teaches that the chromatographic column is an organo- silica grafted C18 resin (See Para 0660… Purification of ApoA-I Mimics prepared according to Example 1 is performed by preparative reverse phase HPLC with a C18 stationary phase (grafted silica, 15 μm particle size, 120 Å pore size) using a water/acetonitrile gradient (with 0.1% TFA counter ion)).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of the combination of Zhang, Ragnar-Tolf and Dadey to include the chromatographic column that is an organo-silica grafted C18 resin, as taught by Dasseux for the benefit of purifying ApoA-I Mimics (Dasseux, Para 0659-0660), allowing for the development of additional peptides that can mimic the activity of ApoA-I in vivo, which are simple and cost-effective to produce. (Dasseux, Para 0008).
Regarding Claim 26, the method of claim 25 is obvious over Zhang in view of Ragnar-Tolf in view of Dadey and further in view of Dasseux.
The combination of Zhang, Ragnar-Tolf and Dadey does not teach that the chromatographic column has an average particle size of about 2 µm to about 20 µm and a pore size of about 100 Å to about 120 Å.
In the analogous art of peptides, compositions thereof, and methods for treating or preventing dyslipidemia, a cardiovascular disease, endothelial dysfunction, a macrovascular disorder, or a microvascular disorder, Dasseux teaches that the chromatographic column has an average particle size of about 2 µm to about 20 µm and a pore size of about 100 Å to about 120 Å (See Para 0660… Purification of ApoA-I Mimics prepared according to Example 1 is performed by preparative reverse phase HPLC with a C18 stationary phase (grafted silica, 15 μm particle size, 120 Å pore size) using a water/acetonitrile gradient (with 0.1% TFA counter ion)).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of the combination of Zhang, Ragnar-Tolf and Dadey to include that the chromatographic column has an average particle size of about 2 µm to about 20 µm and a pore size of about 100 Å to about 120 Å, as taught by Dasseux for the benefit of purifying ApoA-I Mimics (Dasseux, Para 0659-0660), allowing for the development of additional peptides that can mimic the activity of ApoA-I in vivo, which are simple and cost-effective to produce. (Dasseux, Para 0008).
Regarding Claim 28, the method of claim 25 is obvious over Zhang in view of Ragnar-Tolf in view of Dadey and further in view of Dasseux.
Zhang further teach that the degarelix or pharmaceutically acceptable salt thereof containing Compound A (See Para 0079… The fractions containing product, thereby teaching “degarelix”) is applied to the chromatographic column as a solution (See Para 0079… The fractions containing product with the acceptable purity are pooled and desalted using the same column) comprising acetic acid in a concentration of 0.01-1% by volume (See Para 0079… Desalting is performed using buffer A (1% aqueous acetic acid), thereby teaching “0.01-1% by volume”).
Regarding Claim 30, the method of claim 25 is obvious over Zhang in view of Ragnar-Tolf in view of Dadey and further in view of Dasseux.
Zhang further teaches that the degarelix or pharmaceutically acceptable salt thereof containing compound A (See Para 0079… The fractions containing product, thereby teaching “degarelix”) is applied to the chromatographic column as a solution (See Para 0079… The fractions containing product with the acceptable purity are pooled and desalted using the same column) comprising degarelix (See Para 0079… A total of 11.8 g (overall yield 37%) of degarelix is obtained as a fluffy solid, thereby teaching isolating the purified degarelix or pharmaceutically acceptable salt thereof).
While Zhang teaches the amount/yield of the obtained degarelix solution, the combination of Zhang, Ragnar-Tolf, Dadey and Dasseux does not explicitly teach the final concentration of the obtained degarelix solution.
MPEP § 2144.05, Part II, Subpart B holds that a particular parameter that is recognized as a result effective variable (“a variable that achieves a recognized result”) would be one, but not the only motivation for a person of ordinary skill in the art to experiment to reach another workable product or process. In the synthesis of synthetic peptides, the selection of optimal experimental conditions including final purification concentration of the peptides (products) could affect the dosage amounts towards pharmaceutical formulation. Thus, the final concentration of the obtained degarelix solution being at a concentration of about 0.01 mg/mL to about 10 mg/mL is a result effective variable.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to purify the obtained degarelix solution at a concentration of about 0.01 mg/mL to about 10 mg/mL for the benefit of providing degarelix at fractions containing product with the acceptable purity (Zhang, Para 0079), which allows for the provision of a method for the manufacture of degarelix, which is less costly than methods known in the art (Zhang, Para 0008).
Regarding Claim 32, the method of claim 25 is obvious over Zhang in view of Ragnar-Tolf in view of Dadey and further in view of Dasseux.
Zhang further teaches that the purified degarelix or pharmaceutically acceptable salt thereof (See Para 0014… degarelix; the claimed “or a pharmaceutically acceptable salt thereof” is interpreted as optional”) comprises not more than 0.3 wt.% of compound A (referred to as of Ac-D-2Nal-D-Phe(4Cl)-D-3 Pal-Ser-X-D-4Aph(Cbm)-Leu-ILys-Pro-D-Ala-NH2, wherein X is 4-([2-(5-hydantoyl)]-acetylamino)-phenylalanine [Para 0013-0014]) relative to the degarelix or a pharmaceutically acceptable salt thereof (See Para 0014…degarelix prepared by the method of the invention comprising 0.3% by weight or less of Ac-D-2Nal-D-Phe(4Cl)-D-3 Pal-Ser-X-D-4Aph(Cbm)-Leu-ILys-Pro-D-Ala-NH2, wherein X is 4-([2-(5-hydantoyl)]-acetylamino)-phenylalanine, in particular 0.1% by weight or less, most particularly 0.01% by weight or less).
Claim 27 is rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. (US20120041172A1, Submitted in IDS of 11/18/2022) in view of Ragnar-Tolf et al. (US20070264330A1), further in view of Dadey et al. (US20100266655A1) and further in view of Dasseux et al. (US20160324923A1) as applied to claim 25 above, and further in view of Barker et al. (US5384309A).
Regarding Claim 27, the method of claim 25 is obvious over Zhang in view of Ragnar-Tolf in view of Dadey and further in view of Dasseux.
Zhang further teaches an ammonium acetate buffer solution (See Para 0079…buffer C (0.5 M aqueous ammonium acetate)).
The combination of Zhang, Ragnar-Tolf, Dadey and Dasseux does not teach 45mM ammonium acetate.
In the analogous art of peptide derivatives which are useful as inhibitors platelet function mediated by the GP llbllla receptor and for the prevention of thrombus formation, Barker teaches 45mM ammonium acetate (See Col. 21, lines 24-25…The desired title compound is eluted with 45 mM ammonium acetate at pH 7.3).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Zhang, Ragnar-Tolf, Dadey and Dasseux and to incorporate 45mM ammonium acetate, as taught by Barker for the benefit of eluting the desired title compound (Barker, Col. 21, lines 24-25), allowing for the provision of inhibitors which, by blocking the the binding of fibrinogen (and/or related ligands such as fibronectin, vitronectin and von Willebrands factor) to the platelet GP llbllla receptor, antagonize the final common pathway of platelet aggregation and act as potent antithrombotics (Barker, Col. 1, lines 12-18).
Claim 29 is rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. (US20120041172A1, Submitted in IDS of 11/18/2022) in view of Ragnar-Tolf et al. (US20070264330A1), further in view of Dadey et al. (US20100266655A1) and further in view of Dasseux et al. (US20160324923A1) as applied to claim 28 above, and further in view of Chen et al. (US20180371022A1).
Regarding Claim 29, the method of claim 25 is obvious over Zhang in view of Ragnar-Tolf in view of Dadey and further in view of Dasseux.
Zhang further teaches that the degarelix or pharmaceutically acceptable salt thereof containing compound A (See Para 0079… The fractions containing product, thereby teaching “degarelix”) is applied to the chromatographic column as a solution (See Para 0079… The fractions containing product with the acceptable purity are pooled and desalted using the same column) comprising acetic acid in a concentration of 1% by volume (See Para 0079… Desalting is performed using buffer A (1% aqueous acetic acid)).
The combination of Zhang, Ragnar-Tolf, Dadey and Dasseux does not teach “acetic acid in a concentration of 0.05-0.5% by volume”.
In the analogous art of a method of synthesizing linaclotide through completely selective formation of three disulfide bonds, Chen teaches “acetic acid in a concentration of 0.05-0.5% by volume” (See Para 0034…0.1 vol % aqueous acetic acid/acetonitrile is used as a mobile phase).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of the combination of Zhang, Ragnar-Tolf, Dadey and Dasseux to incorporate “acetic acid in a concentration of 0.05-0.5% by volume”, as taught by Chen for the benefit of preparing linaclotide (Chen, Para 0034), allowing for the exploration of a linaclotide synthesis method which is performed under mild conditions, low in cost, high in yield, high in product purity, simple and stable in processes, and suitable for large-scale production (Chen, Para 0006).
Claim 31 is rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. (US20120041172A1, Submitted in IDS of 11/18/2022) in view of Ragnar-Tolf et al. (US20070264330A1), further in view of Dadey et al. (US20100266655A1) and further in view of Dasseux et al. (US20160324923A1) as applied to claim 25 above, and further in view of Firestone et al. (US6613879B1).
Regarding Claim 31, the method of claim 25 is obvious over Zhang in view of Ragnar-Tolf in view of Dadey and further in view of Dasseux.
Zhang further teaches that the mobile phase (See Para 0079…The product is eluted by 24% B+76% A) is performed at a flow rate of about 70 mL/min (See Para 0079…Purification is executed using a step gradient starting with 10% B for 2-3 column volumes, 29% B for 5-7 column volumes and a gradient from 29% B to 50% B over 3 column volumes at a flow rate of 70 ml/min.).
The combination of Zhang, Ragnar-Tolf, Dadey and Dasseux does not teach a flow rate of about 0.7 mL/min.
In the analogous art of a prodrug that is capable of being converted into a drug by the catalytic action of human fibroblast activation protein (FAPalpha), said prodrug having a cleavage site which is recognised by FAPalpha, and said drug being cytotoxic or cytostatic under physiological conditions, Firestone teaches a flow rate of about 0.7 mL/min (See Col. 28, lines 55-59… Separations were performed under isocratic conditions at a flow rate of 0.7 ml/min on a Nucleosil C-18 column, 100 mm longx4 mm I.D. with 5 μm particle size).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of he combination of Zhang, Ragnar-Tolf, Dadey and Dasseux to incorporate a flow rate of about 0.7 mL/min, as taught by Firestone for the benefit of separating Free doxorubicin and doxorubicinpeptide conjugates (Firestone, Col. 28, lines 49-63), allowing for provision of methods and means for improving normal tissue tolerability of cytotoxic or cytostatic agents with known efficacy against a broad range of tumour tissues (Firestone, Col. 2, lines 55-59).
Response to Arguments
Applicant's arguments filed on 04/13/2026, with respect to the 35 U.S.C. §103 rejections on Claims 1-2 and 4-8; and Claim 3 have been fully considered but they are not persuasive.
Applicants respectfully submit that, at the time of the effective filing date, no such method would have been taught or reasonable suggested by the cited prior arts.
Examiner asserts that the Zhang teaches Claim 1 limitations as disclosed in the rejection of Claim 1. The rejection does not rely on the Angeli reference cited in the previous office action; thus a new rejection is applied.
Specifically, Examiner submits under BRI that “a step gradient” teaches “isocratically eluting” as disclosed in the Zhang reference (See Para 0079… Purification is executed using a step gradient starting with 10% B for 2-3 column.
Applicant's arguments filed on 04/13/2026, with respect to the 35 U.S.C. §103 rejections on Claim 3 has been fully considered but they are not persuasive.
Applicants also respectfully submit that one of ordinary skill in the art would not have applied the combined teachings of Zhang et al. and Angeli et al. with those of Ragnar-Tolf et al. and Dadey in such a way as to arrive at Applicants' invention, e.g., as recited in claims 3 and 25-32.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Examiner asserts that the combination of Zhang, Ragnar-Tolf and Dadey teaches Claim 3 limitations as disclosed in the rejection of Claim 3 above.
In the rejection of Claim 3, the Zhang reference was not used to teach that the mobile phase comprises an ammonium acetate buffer solution having a pH of about 10.0 and acetonitrile in a ratio of about 65: 35 (ammonium acetate buffer solution: acetonitrile), but rather, the combination of the Ragnar-Tolf and Dadey teaches that it is known in the art to have a mobile phase comprising an ammonium acetate buffer solution having a pH of about 10.0 and acetonitrile in a ratio of about 65 : 35 (ammonium acetate buffer solution : acetonitrile).
Examiner submits that the 35 U.S.C. §103 rejection on Claim 3 with respect to Applicant’s arguments is maintained
Further, Applicant argues that a judgment on obviousness may involve some level of hindsight reasoning. However, "[d]etermination of obviousness cannot be based on the hindsight combination of components selectively culled from the prior art to fit the parameters of the patented invention." ATD Corp. v. Lydall, Inc., 159 F.3d 534 (Fed. Cir. 1998). Simply stated, "[o]ne cannot use hindsight reconstruction to pick and choose among isolated disclosures in the prior art to deprecate the claimed invention." In re Fine, 837 F.2d 1071 (Fed. Cir. 1988). In the instant case, for at least the reasons discussed above, Applicants respectfully submit that the reconstruction of Applicants' method from selected teachings from Zhang et al., Ragnar-Tolf et al. and Dadey is not reasonably supported by their explicit disclosures, individually or combined. Thus, Applicant respectfully submits that, as of the effective filing date, one of ordinary skill would not have envisioned Applicant's method based on the combined teachings of the cited art without the benefit of Applicant's disclosure. For at least the foregoing reasons, Applicant respectfully submits that the presently claimed invention is patentable over the cited art. Accordingly, withdrawal of the obviousness rejections is respectfully solicited.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Examiner contends that in the instant rejection of Claim 3, the rejection is based solely on the explicit teachings and suggestions within the cited references, which would have been apparent to one of ordinary skill in the art at the time of the invention.
Applicants’ argument does not identify any specific knowledge or technical feature provided in the cited references after (post) the time of the invention; Rather, the Applicant’s argument appears to challenge the application of ordinary skill to infer the combination of Zhang et al., Ragnar-Tolf et al. and Dadey references to teach the limitations of Claim 3.
Examiner contends that such an inference in permissible in the rejection as it is supported by the references cited.
Accordingly, Examiner submits that the 35 U.S.C. §103 rejection on Claim 3 with respect to Applicant’s arguments is maintained
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to OYELEYE ALEXANDER ALABI whose telephone number is (571)272-1678. The examiner can normally be reached on M-F 7:30am-5:30pm.
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/OYELEYE ALEXANDER ALABI/Examiner, Art Unit 1797
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