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 .
Applicant’s 9-4-26 election, without traverse, of the species of buffer system which is “a citrate buffer” and the sub-species of citrate buffer which comprises “trisodium citrate and citric acid as buffers” is acknowledged.
Upon further consideration the species of buffer under examination has been extended to include “an acetate buffer.”
Claims 1-17 are pending and under examination as they read on the species of buffer which is “an acetate buffer” or “a citrate buffer,” and the sub-species of citrate buffer which comprises “trisodium citrate and citric acid as buffers”
The meaning of the instant claims
Claim 1 and dependent claims thereof recite that the composition “…does not substantially comprise a stabilizer.”
According to the specification at page 6-7 bridging paragraph to 1st paragraph on page 7 (emphasis added):
“The ophthalmic composition of the present invention does not substantially comprise a stabilizer. Here, the stabilizer means an additional component comprised in a formulation to prevent a decrease in chemical and physical stability or biological activity of tanfanercept used as an active ingredient. For example, to inhibit the aggregation of a protein in the ophthalmic composition, it is well known that the stabilization of a protein may be ensured using a saccharide such as sucrose or mannitol, or an amino acid-based stabilizer such as proline, arginine, glycine, lysine or methionine. The present invention does not substantially comprise a stabilizer since it had been found from the following embodiment that, unlike the usual cases, such a stabilizer has an adverse effect on the stability of tanfanercept. The buffer or isotonic agent described in the present invention is not included in the stabilizer.
The stabilizer is “not substantially comprised” or “substantially free” means that it is comprised at less than 0.1% (w/v), 0.05% (w/v), 0.03% (w/v), 0.02% (w/v), 0.01% (w/v), 0.005% (w/v) or 0.001% (w/v), and most preferably, not comprised at all.”
Thus, the instant claims, given their broadest reasonable interpretation consistent with the teachings of the instant specification and the knowledge in the prior art, would be understood by the ordinarily skilled artisan to read on a composition comprising < 0.1% (w/v) of “an additional component comprised in a formulation to prevent a decrease in chemical and physical stability or biological activity of tanfanercept used as an active ingredient,” such as < 0.1% (w/v), in total, of a saccharide such as sucrose or mannitol, and/or an amino acid-based stabilizer such as proline, arginine, glycine, lysine or methionine, or any other stabilizer that “prevents a decrease in chemical and physical stability or biological activity of tanfanercept.”
Note that composition components that serve to stabilize something other than the chemical and physical stability, or the biological activity of tanfanercept, per se, are still encompassed in the breadth of the claimed composition.
For example, at para 0004 Kim et al. (20150119338) describes how “ artificial tears are used to complement an ocular tear film or reduce the evaporation of tears to stabilize the tear film,” and “[a] main ingredient of the artificial tear is cellulose ether, carbomer, polyvinyl alcohol, polyvinyl pyrollidone, sodium hyaluronate, or the like, and the artificial tear is prepared by dissolving it in buffer or isotonic saline. These ingredients make the solution viscous to thereby prevent the solution from easily flowing from the eye, prevent the evaporation of tear, and serve as a lubricant;” however, stabilizing the tear film is considered to be outside of stabilizing the chemical and physical stability, or the biological activity of tanfanercept, per se.
Likewise, at para 0088 Kim teaches “surfactant is used to dissolve effective ingredients and stabilize a colloidal dispersion, e.g., a micelle solution, a microemulsion, emulsion, or a suspension;” however, stabilization of a colloidal dispersion is considered to be outside of stabilizing the chemical and physical stability, or the biological activity of tanfanercept, per se.
Thus, the instant claims given their broadest reasonable interpretation consistent with the teachings of the instant specification and the knowledge in the prior art would still encompass in their breadth components such as carbomers and surfactants that do not intrinsically stabilize tanfanercept, per se; rather, they stabilize tear film or stabilize colloidal dispersion properties.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1-5 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Choi et al. (Korean J Ophthalmol 2016;30(4):302-308, cited on an IDS).
Choi teaches the use of “HL036337” (which is the same as tanfanercept) at doses ranging from 0.25 mg/mL to 5 mg/mL for the treatment of dry eye-induced mice wherein HL036337 via topical application to the eye in the presence of a vehicle comprising sodium acetate, pH 5.5 (see page 303, right col., 1st full paragraph; page 305 col. bridging paragraph and Fig. 3). Thus, the HL036337 + vehicle compositions of Choi anticipate claims 1-5.
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.
Claim(s) 1-17 are rejected under 35 U.S.C. 103 as obvious over Kim et al. (20150119338, cited on an IDS) in view of Laurie et al. (WO2018156501, cited on an IDS).
Kim teaches a TNFRI fusion protein, “HL036337,” which is effective for the treatment of dry eye syndrome in a murine model system (see Examples 1-2). At Table 1 Kim describes the TNFRI modifications present in HL036337, and in para 115 indicates that the variants listed in Table 1 were applied to various TNFRIs, including “TNFRI171,” wherein said sequences appear in SEQ ID NOs: 13-30 of the sequence listing. Among the “TNFRI171” sequences set forth in the sequence listing, SEQ ID NOs: 20 has the mutations of the “HL036337” TNFRI fragment of Kim Table 1 and Examples 1 and 2. According to the instant specification at page 3, 3rd full para, Tanfanercept is the same thing as “TNFRI171.”
At para 0084, Kim teaches “[g]enerally, the dosage of the modified TNFRI or modified TNFRI fragment of the present invention, used for treatment or prevention of dry eye syndrome may be varied depending on the kind, age, and weight of subject to be administered, severity of the symptom, desired treatment effect, administrating method, treatment period, and the like….As used herein, the term "pharmaceutically effective amount" refers to the amount which improves dry eye syndrome…. In particular, in the case of topical application to the eye, a medicine containing 0.001~10 w/v % and preferably 0.01~10.0 w.v% of the modified TNFRI or modified TNFRI fragment of the present invention is applied to the eye several times per day….”
Starting at para 0085, Kim teaches various components that can be used for the preparation of compositions that “…may further comprise physiologically compatible vehicles and/or
additives, which are generally selectable in the art, in addition to the modified TNFRI or modified TNFRI fragment of the present invention.”
For example, at paras 85-92 Kim further teaches the following:
“[0085] …The composition according to the present invention may further comprise, as the vehicles and/or additives, an isotonicity agent, a buffer, a surfactant, a stabilization polymer, a preservative, a viscosity increasing agent, antioxidant, and the like, but is not limited thereto. It is obvious to those skilled in the art that other components conventionally used may be further included. In addition, the composition of the present invention may further comprise a surfactant and/or a mitigating agent and/or a stabilization polymer.
[0086] The isotonicity agent is used to adjust tonicity of the composition, preferably tonicity of natural tears used as an ophthalmic composition. For example, the tonicity of the composition may be adjusted similarly to physiological isotonicity by adding sodium chloride, potassium chloride, magnesium chloride, calcium chloride, simple sugars, such as dextrose, fructose, and galactose, and/or simple polyols, such as sugar alcohol, mannitol, sorbitol, xylitol, lactitol, isomalt, and maltitol, or hydrogenated starch hydrolysate to the composition. The amount of this isotonicity agent may be appropriately selected depending on the specific kind of reagent.
[0087] As the buffer, at least one selected from for example sodium phosphate, sodium acetate,
sodium citrate, sodium borate, and boric acid may be used. The buffer may be used to prevent pH change of the composition under storage conditions. The concentration of the buffer is varied depending on the kind of reagent, but may be selected so as to maintain a pH value of 5 to 8, and more preferably 5 to 7.
[0088] The surfactant is used to dissolve effective ingredients and stabilize a colloidal dispersion, e.g., a micelle solution, a microemulsion, emulsion, or a suspension. For example, polysorbate, poloxamer, polyoxyl 40 stearate, polyoxyl caster oil, tyloxapol, triton (e.g., Triton X114), and sorbitan monolaurate may be used.
[0089] As the stabilization polymer, a polyelectrolyte selected from cross-linked polyacrylates, for example, carbomer or Pemulen (product name), specifically, 0.1 to 0.5% (w/w) of carbomer 974P (polyacrylic acid) may be used.
[0090] The preservant is used to prevent microorganism contamination during use of the composition, and for example, benzalkonium chloride, chlorobutanol, benzodedecynium bromide, methyl paraben, propyl paraben, phenylethyl alcohol, edentate disodium, sorbic acid, polyquarternium-1, or other agents known in the art may be used.
[0091] The viscosity increasing agent is used to increase viscosity of a carrier, and examples thereof may include polysaccharides, such as hyaluronic acid and its salts, chondroitin sulfate and its salts, various polymers of dextrans and celluloses; vinyl polymers; acrylic acid polymers, but are not limited thereto.
[0092] The antioxidant may be further added to the composition of the present invention to prevent active ingredients from being oxidized during storage. Examples of the antioxidant may include vitamin E and its analogs, ascorbic acid and its derivatives, and butylated hydroxyanisole (BHA).”
Note that the “stabilization polymer” described in para 0089 of Kim is not considered a “stabilizer” encompassed by the instant claims because such molecules would not be expected to act to preserve the chemical and physical stability or biological activity of tanfanercept. Rather, such carbomers / polyacrylates were well known in the ocular topical art to stabilize the tear film in dry eye syndrome (see Kim at para 0004).
However, Kim does not explicitly teach, e.g., “a stable tanfanercept-containing ophthalmic composition, comprising: tanfanercept and a buffer system of pH 5.0 to pH 6.5, which does not substantially comprise a stabilizer.”
At para 0005-6, Laurie teaches (emphasis added):
“[0005] Polypeptides are increasingly being recognized as potential therapeutic agents. Consequently, there is an increased interest in exploring polypeptides in pharmaceutical research and development. However, polypeptides are notoriously difficult to formulate and additives used to preserve or stabilize such formulations result in, for example, undesired side effects.
SUMMARY
[0006] There is an unmet need for peptide compositions that provide therapeutic amounts of peptides, are stable at room temperature, and contain only trace amounts of stabilizers and/or preservatives, or none at all. To address such needs and others, several embodiments of the present application provide stable polypeptide compositions. Advantageously, in some embodiments, the peptide (or combination of peptides) is stabilized in the compositions of the present application so as to allow for long-term storage and/or delivery over a prolonged period of time. As such, these peptide compositions are stable at non-refrigerated temperatures without the need for reconstitution, and are functional over a range of temperatures, including temperatures ranging from 0-30°C. Indeed, certain embodiments of this application are based, in part, on the surprising and unexpected discovery that dilute peptide compositions including low levels of EDTA in combination with low levels of citrate buffer remain efficacious after storage at room temperature, even though such compositions contain additive levels substantially lower than typically found in polypeptide compositions.”
At para 0015 Laurie further teaches, “[s]ome embodiments provide a method of treating Dry Eye and/or Primary Sjogren's Syndrome comprising administering the compositions disclosed herein to the eye of a subject having Dry Eye and/or Primary Sjogren's Syndrome, where the polypeptide or pharmaceutically acceptable salt thereof is in an amount of 0.005%, or 0.01%....”
With respect to “stabilizing agents” Laurie instructs at 0023 that “The term ‘stabilizing agent’ as used herein shall be given its ordinary meaning and shall include a material that inhibits chemical reactions with a peptide. Stabilizing agents may include, for example, antioxidants such as sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole, butylated hydroxytoluene, and combinations of the foregoing,” and further at para 0048 that:
“Buffers and chelators can stabilize peptide ingredients of compositions by maintaining pH and reducing metal ion mediated degradation of the peptides. In some embodiments, the composition further comprises one or more peptide stabilizing agents in addition to a buffer and/or a chelating agent. In some embodiments, the one or more stabilizing agents in addition to a buffer and/or chelating agent are selected from the group consisting of disaccharides, polysaccharides (e.g., hyaluronic acid), polyols, sugar alcohols, amino acids, proteins (e.g., serum albumin), and combinations thereof. In some embodiments, non-limiting examples of stabilizers include trehalose, sucrose, mannitol, sorbitol, polysorbate 20, polysorbate 80, histidine, glycine, and arginine, and combinations thereof. In an embodiment the composition does not include a stabilizer in addition to a buffering agent and/or a chelator.”
At Examples 1-2, Laurie teaches formulating compositions comprising their Lacripep™ (SEQ ID NO: 1) polypeptide in the presence of a citrate buffer at pH 6.0 or 6.5, but in the absence of stabilizing agent such as disaccharides, polyols, amino acids, etc.
Given the reference teachings it would have been obvious to one of ordinary skill in the art that, among the various buffers taught by Kim for use in preparing a SEQ ID NOs: 20 / “HL036337” composition, a citrate buffer capable of promoting a stable pH around 6.0-6.5 may be optimal, since, as taught by Laurie, the use of such a buffer allows a polypeptide to exhibit good functional activity even when the stabilizers that would typically be presents in a polypeptide composition, such as disaccharides, polyols or amino acids are absent or at most present in only trace amounts as compared to the amounts of stabilizing additives typically found in polypeptide compositions.
With respect to the composition of claim 1 having certain amounts of tanfanercept (see claim 2), as set forth by Kim “in the case of topical application to the eye, a medicine containing 0.001~10 w/v % and preferably 0.01~10.0 w.v% of the modified TNFRI or modified TNFRI fragment.”
With respect to claims 7 and 8, the non-limiting exemplary compositions of Laurie set forth in Tables 1.1 – 1.4 on pages 30-32 include the combination of citric acid (anhydrous) and “sodium citrate (dihydrate),” which is synonymous with “trisodium citrate” as shown below:
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Moreover, the (% w/v) of “citric acid (anhydrous)” and “sodium citrate (dihydrate)” set forth in Tables 1.1 – 1.4 of Laurie is 0.0098 and 0.279, respectively, amounts to 10 mM citrate buffer. Thus, it would have been obvious to one of ordinary skill in the art following the teachings of Kim in view of Laurie to produce a citrate buffered polypeptide composition that there citrate buffer should have features recited in claims 7 and 8.
With respect to claims 9 and 10, Kim teaches the use of an isotonicity agent such as sodium chloride to give their compositions, such as a SEQ ID NOs: 20 / “HL036337” composition,
physiological isotonicity.
Furthermore, with respect to claim 17 and consistent with the teachings of Kim, at paras 80-83 Laurie teaches with sodium chloride as the tonicity agent the osmolality can be adjusted to a desired level, e.g., “…between about 280 mOsm/g and about 320 mOsm/g.”
With respect to compositions exhibit the charge variant features recited in claims 11-16, it appears from the instant specification at working examples 3-4 that when tanfanercept is present in a composition having the elements of claim 6 that said composition will inherently exhibit the charge variant features recited in claims 11-16. Thus, since the preparation of ophthalmic compositions comprising tanfanercept in the presence of a citrate buffer at a pH of 6.0-6.5 would have been obvious to one of ordinary skill in the art knowledgeable of the teachings of Kim in view of Laurie for the reasons set forth above, and since such compositions inherently have the charge variant features recited in claims 11-16, the teachings of Kim in view of Laurie render the claimed compositions prima facie obvious.
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-4 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 18, 20-32 and 34 of copending Application No. 18261368 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because reference claims 18 and 34 in particular recite the various limitations of claims 1-4 in the context of a method of treating dry eye syndrome in a patient wherein an ophthalmic composition comprising tanfanercept is being administered to said patient. Thus, to practice the method of the reference claims the ordinarily skilled artisan must administer the ophthalmic composition of instant claims 1-4. Therefore, the reference claims anticipate the instant claims
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ZACHARY S SKELDING whose telephone number is (571)272-9033. The examiner can normally be reached M-F 9-5 EST.32
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/ZACHARY S SKELDING/Primary Examiner, Art Unit 1644
