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 .
Formal Matters
This office action is issued in response to the claim set filed on 23 February 2024. Claims 41-42, 44-45, 47-50, 52-54, and 58-70 are pending. Claims 41-42, 44-45, 47-50, 52-54, and 58-70 are under consideration in the instant office action. Claims 1-40, 43, 46, 51, 55-57, and 71-120 are canceled.
Information Disclosure Statement
The information disclosure statements (IDSs) submitted on 09 April 2026 are noted and the submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the examiner has considered the references. Signed copies are attached herein.
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.
Claim(s) 41-42, 44-45, 47-50, 52-54, 58-59, 62-63, and 65, is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Christensen et al. (WO2019/048674).
Applicants recite in claim 1 “A method of treating a disease, disorder, or condition characterized by iron deficiency or dysfunctional iron metabolism, the method comprising administering to a subject in need of treatment a stable injectable iron composition comprising iron, a carbohydrate, a stabilizing agent and water.” Dependent claims thereof recite additional features.
Christensen et al. teach a method of treating a disease, disorder, or condition characterized by iron deficiency or dysfunctional iron metabolism comprising administering to a subject in need of treatment a stable injectable (parenteral) iron composition comprising one or more of iron carbohydrate complexes that form a colloidal iron (III) carbohydrate complex (see E1-E9, E24-E36, E43, E49-E52). Iron carbohydrate complex compounds of the present invention include, for example, iron carboxymaltose, iron polyglucose sorbitol carboxymethyl ether complex, iron mannitol complex, iron dextran, iron hydrogenated dextran, iron oxidized dextran, iron carboxyalkylated reduced oligo- and polysaccharides, iron sucrose, iron gluconate, iron dextrin, iron hydrogenated dextrin, iron oxidized dextrin, iron polymaltose, iron hydrogenated polymaltose, iron oligomaltose, hydrogenated iron oligomaltose, iron polyisomaltose, iron hydrogenated polyisomaltose, iron hydrogenated oligosaccharides such as iron hydrogenated oligoisomaltose, iron hydroxyethyl starch, iron sorbitol, iron dextran glucoheptonic acid (e.g., gleptoferron) and a mixture of two or more thereof. According to particular embodiments, the iron carbohydrate complex compound of the present invention is selected from iron carboxymaltose, iron polyglucose sorbitol carboxymethyl ether complex, iron mannitol complex, iron dextran, iron hydrogenated dextran, iron sucrose, iron gluconate, iron dextrin, iron hydrogenated oligoisomaltose and a mixture of two or more thereof. The carbohydrate in iron carbohydrate complex compounds of the invention typically has a weight average molecular weight (Mw) of from 500 to 80,000 Da, such as from 800 to 40,000 Da or from 800 to 10,000 Da and in particular from 800 to 3,000 Da. The apparent molecular weight (Mp) of the iron carbohydrate complex compounds of the invention is typically in the range of from 800 to 800.000 Da, such as from 10,000 to 500,000 Da or from 20,000 to 400,000 Da or from 50,000 to 300,000 Da and in particular from 90,000 to 200,000 Da. The apparent molecular weight Mp can be determined by gel-permeation chromatography using, e.g., dextran standards. See, for example, the method described in Jahn et al., Eur J Pharm Biopharm 201 1 , 78, 480-491. The amount of dimer in carbohydrate preparations which are (optionally reduced and/or oxidized and/or derivatized) oligosaccharide or polysaccharide preparations was found to be a key factor with regard to the stability of the iron carbohydrate complex compounds prepared therefrom. See WO 2010/108493 A1. In iron carbohydrate complex compounds of the invention where the carbohydrate is an (optionally reduced and/or oxidized and/or derivatized) oligosaccharide or polysaccharide preparation, the content of dimer saccharides in said preparation is therefore preferably 2.9 wt-% or less, in particular 2.5 wt-% or less, and especially 2.3 wt-% or less, based on the total weight of the carbohydrate. It is also preferred that the content of monomer saccharide in the carbohydrate preparation is 0.5 wt-% or less, based on the total weight of the carbohydrate. This reduces the risk of toxic effects caused by free iron ions released from compounds of monomer and iron, especially when present in preparations for parenteral administration. Low amounts of dimer saccharides and/or monomer saccharides as indicated above can be obtained, e.g., by removing said smaller saccharide molecules from a carbohydrate preparation by a purification method such as membrane filtration, for examples using membranes having cut-off values in the range of 340-800 Da (see pages 14-15). Accordingly, in preferred embodiments of the invention, the iron complex compound is an iron hydrogenated oligoisomaltose, in particular an iron(III) hydrogenated oligoisomaltose, wherein the majority (such as at least 60%, e.g. from 70 to 80%) of the hydrogenated oligoisomaltoside molecules has 3-6 monosaccharide units, such as iron(III) isomaltoside 1000 (INN name: ferric derisomaltose). Iron isomaltosides are typically characterized by a strong colloidal complex of iron oxide-hydroxide and hydrogenated isomaltose (isomaltoside) chains resulting in a gradual release of iron (see page 16).
Christensen et al. teach an iron complex compound according to any one of afore-mentioned three embodiments, or a composition thereof, can be used for treatment or prophylaxis of iron- deficiency in a subject. The subject may be a human subject or a non-human animal, in particular a non-human mammal, e.g. a pig, horse, dog, cat, camel, sheep, goat or cow. Preferably, the subject is a human subject. An iron complex compound according to any one of afore-mentioned three embodiments can be formulated, and used, for various ways of administration, for example for intramuscular administration or for intravenous administration (see page 26). Compositions for parenteral administration can have the form of injectable or infusible solutions, suspensions or emulsions in liquid carriers such as, for example, sterile water, saline or other buffered aqueous solutions. Such compositions may comprise further additives such as stabilizing agents (e.g., citric acid, citrate or gluconate), antibacterial agents (e.g., benzyl alcohol or phenol), antioxidants (e.g., ascorbic acid or sodium bisulfite) and/or agents for adjusting tonicity (e.g., sodium chloride or dextrose). Alternatively, the iron complex compound may be presented in the form of a powder for constitution with sterile water or saline or another suitable liquid before use. Compositions for parenteral administration may also be formulated as implantable or injectable depot compositions, for example with suitable polymeric or hydrophobic carriers. In particular embodiments, the compositions of the invention are formulated for parenteral administration (e.g., intramuscular injection, subcutaneous injection, intravenous injection or intravenous infusion, optionally as bolus injection or infusion) such as, for example, as injectable or infusible solutions in an aqueous carrier such as saline. The invention provides iron complex compounds of the invention as described herein for therapeutic use. Accordingly, methods for administering an iron complex compound of the invention to a subject are described herein. The iron complex compound can be administered, for example, orally or parenterally (such as by intramuscular injection, subcutaneous injection, intravenous injection or intravenous infusion, optionally as bolus injection or infusion). The iron complex compound can be administered in the form of a composition thereof as described herein. In particular, iron complex compounds of the invention can be used for the treatment or prophylaxis of iron-deficiency in a subject. The subject can be selected from, for example, pig, horse, dog, cat, camel, sheep, goat, cow and human. The iron complex compounds of the invention are also useful for the treatment or prophylaxis of iron-deficiency in infants such as, e.g., children, piglets, foals, camel foals, lambs, goat kids or calfs. The term infant as used herein includes non-adult offspring starting from neonates. Iron deficiency that can be treated or prevented by administering an iron complex compound of the invention can be, for example, iron deficiency associated with chronic blood loss, acute blood loss, pregnancy, childbirth, lactation, childhood development, heavy uterine bleeding, menstruation, gastrointestinal bleeding, chronic internal bleeding, inflammatory bowel disease, congestive heart failure, restless leg syndrome, parasitic infections, lost or impaired kidney function such as due to chronic kidney disease or kidney failure, dialysis, surgery, chronic ingestion of agents such as alcohol, salicylates, steroids, non-steroidal anti-inflammatory agents, erythropoiesis stimulating agents (ESAs) or drugs inhibiting iron absorption (see pages 26-28). The amount of iron in the iron carbohydrate complex compound of the invention, determined for dry matter, is typically in the range of from 10 to 50 wt-%, such as from 15 to 45 wt-% and in particular from 24 to 32 wt-%. The concentration of iron in iron complex solutions for injection according to the invention is typically in the range of from 25 to 300 mg/ml, such as from 50 to 200 mg/ml. In preferred particular embodiments of iron complex solutions for injection according to the invention, the concentration of iron is about 100 mg/ml or about 200 mg/ml (see page 15). Metals such as iron, arsenic, chromium, lead, mercury, cadmium and aluminum exist in different forms (elemental form, salts, complex compounds) (see page 5). An iron complex compound according to any one of said 1 st to 9th embodiments can be formulated, and used, for various ways of administration, for example for intramuscular administration or for intravenous administration. Iron complex compounds according to any one of said 1 st to 3rd embodiments are preferably formulated, and used, for intravenous administration. Iron complex compounds according to any one of said 4th to 9th embodiments are preferably formulated, and used, for intramuscular administration (see page 25). Preferably, the pH of the aqueous solution in step (1 ) is acidic, e.g. the solution is at a pH of 2 or lower, so as to prevent the precipitation of iron hydroxides. The addition of a base in step (2) is preferably performed in a slow or gradual manner so as to increase the pH to, for example, a pH of 5 or more, such as up to pH 1 1 , 12, 13 or 14. Such gradual increase can be achieved by first adding a weak base (e.g., an alkali metal carbonate or alkaline earth metal carbonate such as sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate, or ammonia) to increase the pH, e.g., up to pH 2- 4, e.g., up to 2-3, and then further increasing the pH by adding a strong base (e.g., an alkali metal hydroxide or alkaline earth metal hydroxide such as sodium hydroxide, potassium hydroxide, calcium hydroxide or magnesium hydroxide) (see page 18). Suitable ligands for ligand-substituted oxo-hydroxy iron complex compounds of the invention include, for example, carboxylic acids, such as adipic acid, glutaric acid, tartaric acid, malic acid, succinic acid, aspartic acid, pimelic acid, citric acid, gluconic acid, lactic acid and benzoic acid; food additives such as maltol, ethyl maltol and vanillin; anions with ligand properties such as bicarbonate, sulphate and phosphate; mineral ligands such as silicate, borate, molybdate and selenate; amino acids, in particular proteinogenic amino acids, such as tryptophan, glutamine, proline, valine and histidine; and nutrient-based ligands such as folate, ascorbate, pyridoxine and niacin; as well as a mixtures of two or more thereof (see page 20). Carbohydrates which may be used as ligands in iron carbohydrate complex compounds of the present invention include, for example, monosaccharides; disaccharides, e.g. sucrose and maltose; oligosaccharides and polysaccharides, etc. In preferred embodiments, the carbohydrate is carboxymaltose, polyglucose sorbitol carboxymethyl ether, mannitol, dextran, hydrogenated dextran, sucrose, gluconate, dextrin, hydrogenated oligoisomaltose (oligoisomaltoside) or a mixture of two or more thereof (see page 4).
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.
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 41-42, 44-45, 47-50, 52-54, and 58-70 are rejected under 35 U.S.C. 103 as being unpatentable over Christensen et al. (WO2019/048674) in view of Bock et al. (US Patent No. 10,899,826) and MacLeod et al. (US 2003/0114430).
Applicants’ claims
Applicants recite in claim 1 “A method of treating a disease, disorder, or condition characterized by iron deficiency or dysfunctional iron metabolism, the method comprising administering to a subject in need of treatment a stable injectable iron composition comprising iron, a carbohydrate, a stabilizing agent and water..” Dependent claims thereof recite additional features.
Determination of the Scope and Content of the Prior Art
(MPEP 2141.01)
The teachings of Christensen et al. are in detail described above and are incorporated herein by reference.
Ascertainment of the Difference Between Scope of the Prior Art and the Claims
(MPEP 2141.02)
Christensen et al. teach claim 70 in obvious manner as Christensen et al. teach the average molecular weight of the colloidal iron (III) complex in obvious and overlapping manner. Christensen et al. do not specifically teach the limitations of claims 60-61, 64, and 66-70. Specifically, the volume amounts recited in claim 60, L-histidine, and the amounts of sucrose, L-histidine, and sodium hydroxide as recited in claims 64 and 66-69. These deficiencies are cured by the teachings of Bock et al. and MacLeod et al.
Bock et al. teach pharmaceutical compositions including a plurality of IgG2 anti-CGRP antagonist antibodies comprising a high content of particular IgG2 disulfide isomers, and methods of using the same (see abstract). In some embodiments of any of the compositions provided herein, the composition is suitable for subcutaneous or intravenous administration to a subject. In some embodiments, the container comprises less than about 2 mL of the pharmaceutical composition. In some embodiments, the container comprises 1.5 mL of the pharmaceutical composition (see column 4, lines 30-36). In some embodiments, the sugar or sugar alcohol is selected from the group consisting of sorbitol, sucrose, trehalose, and mannitol (column 3, lines 35-37). In some embodiments, the buffering agent comprises histidine, arginine, glycine, asparagine, or a combination thereof (see column 352-54). Also provided herein is a pre-filled syringe comprising about 1.5 mL of a liquid pharmaceutical composition, wherein the liquid pharmaceutical composition comprises about 225 mg fremanezumab, about 0.204 mg disodium ethylenediaminetetraacetic acid dihydrate (EDTA), about 0.815 mg L-histidine, about 3.93 mg L-histidine hydrochloride monohydrate, about 0.3 mg polysorbate-80, about 99 mg sucrose, and water for injection, at a pH of about 5.5, wherein at least about 70% of the fremanezumab in the liquid pharmaceutical composition is of the IgG2-B disulfide isoform. Also provided herein is an autoinjector comprising about 1.5 mL of a liquid pharmaceutical composition, wherein the liquid pharmaceutical composition comprises about 225 mg fremanezumab, about 0.204 mg disodium ethylenediaminetetraacetic acid dihydrate (EDTA), about 0.815 mg L-histidine, about 3.93 mg L-histidine hydrochloride monohydrate, about 0.3 mg polysorbate-80, about 99 mg sucrose, and water for injection, at a pH of about 5.5, wherein at least about 70% of the fremanezumab in the liquid pharmaceutical composition is of the IgG2-B disulfide isoform (column 4, lines 37-57). In some embodiments, the pharmaceutical compositions described herein include a sugar (e.g., a non-reducing sugar) or a sugar alcohol. Exemplary sugars and sugar alcohols include sorbitol, sucrose, trehalose (e.g., trehalose dihydrate), and mannitol. In some embodiments, the pharmaceutical composition is liquid, and the sugar or sugar alcohol is present in the pharmaceutical composition at a concentration of from about 1 mg/mL to about 500 mg/mL, from about 10 mg/mL to about 200 mg/mL, from about 10 mg/mL to about 100 mg/mL, or from about 50 mg/mL to about 150 mg/mL. In some embodiments, the sugar (e.g., sucrose) or sugar alcohol is present in the pharmaceutical composition at a concentration of from about 65 mg/mL to about 90 mg/mL. For example, in some embodiments, the pharmaceutical composition is liquid, and the sugar or sugar alcohol (e.g., sucrose or trehalose) is present in the pharmaceutical composition at a concentration of about 65 mg/mL, 66 mg/mL, 67 mg/mL, 68 mg/mL, 69 mg/mL, 70 mg/mL, 71 mg/mL, 72 mg/mL, 73 mg/mL, 74 mg/mL, 75 mg/mL, 76 mg/mL, 77 mg/mL, 78 mg/mL, 79 mg/mL, 80 mg/mL, 81 mg/mL, 82 mg/mL, 83 mg/mL, 84 mg/mL, 85 mg/mL, 86 mg/mL, 87 mg/mL, 88 mg/mL, 89 mg/mL, or 90 mg/mL. In some embodiments, the pharmaceutical composition is liquid and includes about 66 mg/mL sucrose. In some embodiments, the pharmaceutical composition is liquid and includes a concentration of sugar (e.g., sucrose) or sugar alcohol of from about 0.5% (w/v) to about 10% (w/v), from about 1.0% (w/v) to about 10% (w/v), from about 5.0% (w/v) to about 10.0% (w/v), or from about 5.0% (w/v) to about 7.0% (w/v). In some embodiments, the pharmaceutical composition is liquid and includes a concentration of sugar (e.g., sucrose) or sugar alcohol of about 1.0% (w/v), about 2.0% (w/v), about 3.0% (w/v), about 4.0% (w/v), about 5.0% (w/v), about 6.0% (w/v), about 7.0% (w/v), about 8.0% (w/v), about 9.0% (w/v), about 10.0% (w/v). In some embodiments, the pharmaceutical composition is liquid and includes a concentration of sugar (e.g., sucrose) or sugar alcohol of about 6.1% (w/v), about 6.2% (w/v), about 6.3% (w/v), about 6.4% (w/v), about 6.5% (w/v), about 6.6% (w/v), about 6.7% (w/v), about 6.8% (w/v), about 6.9% (w/v), or about 7.0% (w/v). In some embodiments, the pharmaceutical composition is liquid and includes about 6.6% (w/v) sucrose (see column 17, lines 51-67 and column 18, lines 1-26). In some embodiments, the pharmaceutical composition is liquid and includes a concentration of a buffering agent (e.g., including both an acid and its conjugate base (e.g., L-histidine and L-histidine hydrochloride monohydrate)) of from about 0.1 mg/mL to about 10 mg/mL, from about 1.0 mg/mL to about 10.0 mg/mL, from about 1.0 mg/mL to about 5.0 mg/mL, or from about 2.5 mg/mL to about 5.0 mg/mL. In some embodiments, the pharmaceutical composition is a liquid and includes a buffering agent (e.g., including both an acid and its conjugate base (e.g., L-histidine and L-histidine hydrochloride monohydrate)) at a concentration of about 1.0 mg/mL, about 1.5 mg/mL, about 2.0 mg/mL, about 2.5 mg/mL, about 3.0 mg/mL, about 3.5 mg/mL, about 4.0 mg/mL, about 4.5 mg/mL, or about 5.0 mg/mL (see column 21, lines 6-20). In some embodiments, the pharmaceutical compositions described herein may have any suitable pH for therapeutic efficacy, safety and/or storage. For example, the pH of a liquid pharmaceutical composition may be from about 4 to about 9, from about 5 to about 8, from about 5 to about 6, from about 5 to about 7, or from about 6 to about 8. In some embodiments, a pharmaceutical composition described herein has a pH of about 3.0, about 3.5, about 4.0, about 4.5, about 5.0, about 5.5, about 6.0, about 6.5, about 7.0, about 7.5, about 8.0, about 8.5, about 9.0, about 9.5 or about 10 (or the pH of the pharmaceutical composition may be higher or lower). In some embodiments, a pharmaceutical composition described herein has a pH of from about 5 to about 6 (e.g., 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, or 6.0). In some embodiments, a pharmaceutical composition described herein has a pH of about 5.0±0.3. In some embodiments, a pharmaceutical composition described herein has a pH of about 5.5±0.3. In some embodiments, a pharmaceutical composition described herein has a pH of about 6.0±0.3. In some embodiments, a pharmaceutical composition described herein has a pH of about 6.5±0.3 (column 21, lines 21-40).
MacLeod et al. teach a parenterally deliverable composition is provided, comprising an aqueous medium having dispersed therein, in solid particulate form, a steroidal drug in a therapeutically effective amount. The aqueous medium comprises one or more wetting and/or suspending agents in an amount effective to provide controlled flocculation of the drug, at least one of the wetting and/or suspending agents being susceptible to oxidative degradation. The composition further comprises, as a component thereof or as an adjunct thereto, means for protecting the oxidative degradation susceptible agent from oxidative degradation (see abstract). Preferably a composition of the invention has a pH of about 3 to about 7. An advantage of the invention is that pH of the composition can often be controlled within a narrower range than hitherto, as a result of reduced oxidative degradation of certain formulation ingredients. For example, in a medroxyprogesterone acetate composition as described herein, pH can typically be controlled within a range of about 3 pH units, e. g., about 4 to about 7, more preferably within a range of about 2.5 pH units, e. g., about 4.5 to about 7, and even more preferably within a range of about 2 pH units, e. g., about 5 to about 7, over a prolonged shelf life (paragraph 0081). MacLeod et al. teach in example 3 an antioxidant or a chelating agent was added to samples of commercial Depo-Provera® formulation to study effects of these agents on stability of the product. The antioxidant used was Trolox®, 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid 97% (Aldrich), and the chelating agent used was DTPA pentasodium salt 40% in water (J. T. Baker), diluted with water to 100 mg DTPA/ml. Under constant stirring, bulk Depo-Provera suspension was pipetted in an amount of 1.1 ml in to each of 14 vials. In to each of 4of these vials (“set 2”) had previously been placed 1 mg of Trolox. In to each of another 4 vials (“set 3”), after addition of the suspension, was added 10 μl of diluted DTPA. Contents of all vials containing Depo-Provera plus Trolox or DTPA, and of 4 additional vials (“set 1”) containing only Depo-Provera, were adjusted to a pH of 6.3 to 6.9 with 0.2N hydrochloric acid or 12.5 mg/ml sodium hydroxide solution. The remaining 2 vials containing only Depo-Provera did not have their contents pH-adjusted. These are denoted the “control 0” vials. Half of each of the “set 1”, “set 2”, “set 3” and “control 0” vials were fitted with Helvoet stoppers and capped, and the remaining half were fitted with Daikyo stoppers and capped. The “control 0” vials were placed in a freezer. The other vials were placed in a Fisher Isotemp® vacuum oven, Model 281, set at 85° C. Samples were removed from the oven or freezer after 10 days and resuspended by shaking prior to measurement of pH and bulk solution polysorbate 80 content by the procedures described in Example 1 (see paragraphs 0107-0108).
Finding of Prima Facie Obviousness Rational and Motivation
(MPEP 2142-2143)
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the instant invention to modify the teachings of Christensen et al. by including sucrose, L-histidine in amounts as recited in claims 61 and 66-69 to prepare a solution with final volume as recited in claim 60 because Bock et al. teach pharmaceutical compositions including a plurality of IgG2 anti-CGRP antagonist antibodies comprising a high content of particular IgG2 disulfide isomers, and methods of using the same (see abstract). In some embodiments of any of the compositions provided herein, the composition is suitable for subcutaneous or intravenous administration to a subject. In some embodiments, the container comprises less than about 2 mL of the pharmaceutical composition. In some embodiments, the container comprises 1.5 mL of the pharmaceutical composition (see column 4, lines 30-36). In some embodiments, the sugar or sugar alcohol is selected from the group consisting of sorbitol, sucrose, trehalose, and mannitol (column 3, lines 35-37). In some embodiments, the buffering agent comprises histidine, arginine, glycine, asparagine, or a combination thereof (see column 352-54). Also provided herein is a pre-filled syringe comprising about 1.5 mL of a liquid pharmaceutical composition, wherein the liquid pharmaceutical composition comprises about 225 mg fremanezumab, about 0.204 mg disodium ethylenediaminetetraacetic acid dihydrate (EDTA), about 0.815 mg L-histidine, about 3.93 mg L-histidine hydrochloride monohydrate, about 0.3 mg polysorbate-80, about 99 mg sucrose, and water for injection, at a pH of about 5.5, wherein at least about 70% of the fremanezumab in the liquid pharmaceutical composition is of the IgG2-B disulfide isoform. Also provided herein is an autoinjector comprising about 1.5 mL of a liquid pharmaceutical composition, wherein the liquid pharmaceutical composition comprises about 225 mg fremanezumab, about 0.204 mg disodium ethylenediaminetetraacetic acid dihydrate (EDTA), about 0.815 mg L-histidine, about 3.93 mg L-histidine hydrochloride monohydrate, about 0.3 mg polysorbate-80, about 99 mg sucrose, and water for injection, at a pH of about 5.5, wherein at least about 70% of the fremanezumab in the liquid pharmaceutical composition is of the IgG2-B disulfide isoform (column 4, lines 37-57). In some embodiments, the pharmaceutical compositions described herein include a sugar (e.g., a non-reducing sugar) or a sugar alcohol. Exemplary sugars and sugar alcohols include sorbitol, sucrose, trehalose (e.g., trehalose dihydrate), and mannitol. In some embodiments, the pharmaceutical composition is liquid, and the sugar or sugar alcohol is present in the pharmaceutical composition at a concentration of from about 1 mg/mL to about 500 mg/mL, from about 10 mg/mL to about 200 mg/mL, from about 10 mg/mL to about 100 mg/mL, or from about 50 mg/mL to about 150 mg/mL. In some embodiments, the sugar (e.g., sucrose) or sugar alcohol is present in the pharmaceutical composition at a concentration of from about 65 mg/mL to about 90 mg/mL. For example, in some embodiments, the pharmaceutical composition is liquid, and the sugar or sugar alcohol (e.g., sucrose or trehalose) is present in the pharmaceutical composition at a concentration of about 65 mg/mL, 66 mg/mL, 67 mg/mL, 68 mg/mL, 69 mg/mL, 70 mg/mL, 71 mg/mL, 72 mg/mL, 73 mg/mL, 74 mg/mL, 75 mg/mL, 76 mg/mL, 77 mg/mL, 78 mg/mL, 79 mg/mL, 80 mg/mL, 81 mg/mL, 82 mg/mL, 83 mg/mL, 84 mg/mL, 85 mg/mL, 86 mg/mL, 87 mg/mL, 88 mg/mL, 89 mg/mL, or 90 mg/mL. In some embodiments, the pharmaceutical composition is liquid and includes about 66 mg/mL sucrose. In some embodiments, the pharmaceutical composition is liquid and includes a concentration of sugar (e.g., sucrose) or sugar alcohol of from about 0.5% (w/v) to about 10% (w/v), from about 1.0% (w/v) to about 10% (w/v), from about 5.0% (w/v) to about 10.0% (w/v), or from about 5.0% (w/v) to about 7.0% (w/v). In some embodiments, the pharmaceutical composition is liquid and includes a concentration of sugar (e.g., sucrose) or sugar alcohol of about 1.0% (w/v), about 2.0% (w/v), about 3.0% (w/v), about 4.0% (w/v), about 5.0% (w/v), about 6.0% (w/v), about 7.0% (w/v), about 8.0% (w/v), about 9.0% (w/v), about 10.0% (w/v). In some embodiments, the pharmaceutical composition is liquid and includes a concentration of sugar (e.g., sucrose) or sugar alcohol of about 6.1% (w/v), about 6.2% (w/v), about 6.3% (w/v), about 6.4% (w/v), about 6.5% (w/v), about 6.6% (w/v), about 6.7% (w/v), about 6.8% (w/v), about 6.9% (w/v), or about 7.0% (w/v). In some embodiments, the pharmaceutical composition is liquid and includes about 6.6% (w/v) sucrose (see column 17, lines 51-67 and column 18, lines 1-26). In some embodiments, the pharmaceutical composition is liquid and includes a concentration of a buffering agent (e.g., including both an acid and its conjugate base (e.g., L-histidine and L-histidine hydrochloride monohydrate)) of from about 0.1 mg/mL to about 10 mg/mL, from about 1.0 mg/mL to about 10.0 mg/mL, from about 1.0 mg/mL to about 5.0 mg/mL, or from about 2.5 mg/mL to about 5.0 mg/mL. In some embodiments, the pharmaceutical composition is a liquid and includes a buffering agent (e.g., including both an acid and its conjugate base (e.g., L-histidine and L-histidine hydrochloride monohydrate)) at a concentration of about 1.0 mg/mL, about 1.5 mg/mL, about 2.0 mg/mL, about 2.5 mg/mL, about 3.0 mg/mL, about 3.5 mg/mL, about 4.0 mg/mL, about 4.5 mg/mL, or about 5.0 mg/mL (see column 21, lines 6-20). In some embodiments, the pharmaceutical compositions described herein may have any suitable pH for therapeutic efficacy, safety and/or storage. For example, the pH of a liquid pharmaceutical composition may be from about 4 to about 9, from about 5 to about 8, from about 5 to about 6, from about 5 to about 7, or from about 6 to about 8. In some embodiments, a pharmaceutical composition described herein has a pH of about 3.0, about 3.5, about 4.0, about 4.5, about 5.0, about 5.5, about 6.0, about 6.5, about 7.0, about 7.5, about 8.0, about 8.5, about 9.0, about 9.5 or about 10 (or the pH of the pharmaceutical composition may be higher or lower). In some embodiments, a pharmaceutical composition described herein has a pH of from about 5 to about 6 (e.g., 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, or 6.0). In some embodiments, a pharmaceutical composition described herein has a pH of about 5.0±0.3. In some embodiments, a pharmaceutical composition described herein has a pH of about 5.5±0.3. In some embodiments, a pharmaceutical composition described herein has a pH of about 6.0±0.3. In some embodiments, a pharmaceutical composition described herein has a pH of about 6.5±0.3 (column 21, lines 21-40). One of ordinary skill in the art would have been motivated to do so because Bock et al. clearly demonstrated the use of sucrose and L-histidine in overlapping amounts as pharmaceutically acceptable stabilizing agent and buffering agents respectively in preparation of injectable or parenteral compositions containing active agents. It is within the purview of one of ordinary skill in the art to optimize the amount or concentrations of ingredients since amount or concentrations of ingredients are result effective parameters. Furthermore, the selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945) (Claims to a printing ink comprising a solvent having the vapor pressure characteristics of butyl carbitol so that the ink would not dry at room temperature but would dry quickly upon heating were held invalid over a reference teaching a printing ink made with a different solvent that was nonvolatile at room temperature but highly volatile when heated in view of an article which taught the desired boiling point and vapor pressure characteristics of a solvent for printing inks and a catalog teaching the boiling point and vapor pressure characteristics of butyl carbitol.) In the case where the claimed range of the amount of ingredients "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985) (Court held as proper a rejection of a claim directed to an alloy of "having 0.8% nickel, 0.3% molybdenum, up to 0.1% iron, balance titanium" as obvious over a reference disclosing alloys of 0.75% nickel, 0.25% molybdenum, balance titanium and 0.94% nickel, 0.31% molybdenum, balance titanium. Furthermore, differences in concentration will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical. "[W]here the general conditions of a claim are teach in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233,235 (CCPA 1955). "A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton." KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 421, 82 USPQ2d 1385, 1397 (2007). "[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle." Id. at 420, 82 USPQ2d 1397. Office personnel may also take into account "the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at 418, 82 USPQ2d at 1396. A person of ordinary skill in the art would have had a reasonable chance of success in combining the teachings of Christensen et al. and Bock et al. because both references are drawn to the preparation of injectable compositions comprising substantially similar ingredients.
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the instant invention to modify the teachings of Christensen et al. and Bock et al. by incorporating sodium hydroxide in amounts as recited because MacLeod et al. teach a parenterally deliverable composition is provided, comprising an aqueous medium having dispersed therein, in solid particulate form, a steroidal drug in a therapeutically effective amount. The aqueous medium comprises one or more wetting and/or suspending agents in an amount effective to provide controlled flocculation of the drug, at least one of the wetting and/or suspending agents being susceptible to oxidative degradation. The composition further comprises, as a component thereof or as an adjunct thereto, means for protecting the oxidative degradation susceptible agent from oxidative degradation (see abstract). Preferably a composition of the invention has a pH of about 3 to about 7. An advantage of the invention is that pH of the composition can often be controlled within a narrower range than hitherto, as a result of reduced oxidative degradation of certain formulation ingredients. For example, in a medroxyprogesterone acetate composition as described herein, pH can typically be controlled within a range of about 3 pH units, e. g., about 4 to about 7, more preferably within a range of about 2.5 pH units, e. g., about 4.5 to about 7, and even more preferably within a range of about 2 pH units, e. g., about 5 to about 7, over a prolonged shelf life (paragraph 0081). MacLeod et al. teach in example 3 an antioxidant or a chelating agent was added to samples of commercial Depo-Provera® formulation to study effects of these agents on stability of the product. The antioxidant used was Trolox®, 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid 97% (Aldrich), and the chelating agent used was DTPA pentasodium salt 40% in water (J. T. Baker), diluted with water to 100 mg DTPA/ml. Under constant stirring, bulk Depo-Provera suspension was pipetted in an amount of 1.1 ml in to each of 14 vials. In to each of 4of these vials (“set 2”) had previously been placed 1 mg of Trolox. In to each of another 4 vials (“set 3”), after addition of the suspension, was added 10 μl of diluted DTPA. Contents of all vials containing Depo-Provera plus Trolox or DTPA, and of 4 additional vials (“set 1”) containing only Depo-Provera, were adjusted to a pH of 6.3 to 6.9 with 0.2N hydrochloric acid or 12.5 mg/ml sodium hydroxide solution. The remaining 2 vials containing only Depo-Provera did not have their contents pH-adjusted. These are denoted the “control 0” vials. Half of each of the “set 1”, “set 2”, “set 3” and “control 0” vials were fitted with Helvoet stoppers and capped, and the remaining half were fitted with Daikyo stoppers and capped. The “control 0” vials were placed in a freezer. The other vials were placed in a Fisher Isotemp® vacuum oven, Model 281, set at 85° C. Samples were removed from the oven or freezer after 10 days and resuspended by shaking prior to measurement of pH and bulk solution polysorbate 80 content by the procedures described in Example 1 (see paragraphs 0107-0108). One of ordinary skill in the art would have been motivated to do so because MacLeod et al. clearly demonstrated the use of sodium hydroxide a conventionally known pH adjusting agent to adjust the pH of a parenteral or injectable composition in preparation of injectable or parenteral compositions containing active agents. It is within the purview of one of ordinary skill in the art to optimize the amount or concentrations of sodium hydroxide since amount or concentrations of ingredients are result effective parameters. Furthermore, the selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945) (Claims to a printing ink comprising a solvent having the vapor pressure characteristics of butyl carbitol so that the ink would not dry at room temperature but would dry quickly upon heating were held invalid over a reference teaching a printing ink made with a different solvent that was nonvolatile at room temperature but highly volatile when heated in view of an article which taught the desired boiling point and vapor pressure characteristics of a solvent for printing inks and a catalog teaching the boiling point and vapor pressure characteristics of butyl carbitol.) In the case where the claimed range of the amount of ingredients "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985) (Court held as proper a rejection of a claim directed to an alloy of "having 0.8% nickel, 0.3% molybdenum, up to 0.1% iron, balance titanium" as obvious over a reference disclosing alloys of 0.75% nickel, 0.25% molybdenum, balance titanium and 0.94% nickel, 0.31% molybdenum, balance titanium. Furthermore, differences in concentration will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical. "[W]here the general conditions of a claim are teach in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233,235 (CCPA 1955). "A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton." KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 421, 82 USPQ2d 1385, 1397 (2007). "[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle." Id. at 420, 82 USPQ2d 1397. Office personnel may also take into account "the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at 418, 82 USPQ2d at 1396. A person of ordinary skill in the art would have had a reasonable chance of success in combining the teachings of Christensen et al., Bock et al., MacLeod et al. because all of the references are drawn to the preparation of injectable compositions comprising substantially similar ingredients.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Conclusion
No claims are allowed.
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/TIGABU KASSA/Primary Examiner, Art Unit 1619
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