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 .
Priority
This Application is a 371 of PCT/EP2021/056542, March 13, 2020, and claims foreign priority to EP20163014.2, filed March 13, 2020 with the European Patent Office.
Claim Status
Claims 1-7 and 9-20 are currently pending.
In response to a Restriction/ Election requirement mailed June 17, 2025, the Application elected Group I, claims 1-12 and 16-20 for examination without traverse. The Applicant elected a protein drug, histidine malate, polysorbate 20, a liquid composition, and intravenous administration as the species for examination. (Remarks, p. 5-6).
Claims 1-7, 9-12 and 16-20 read on the elected invention and are currently active and subject to examination.
Claims 13-15 are withdrawn.
Claim Rejections – Withdrawn – Overcome by Amendment
The rejection of claims 1-12 and 17-20 under 35 U.S.C. 102(a)(1) as being anticipated by Sigl (WO2019106206A1) (of record, cited in the last office action) is withdrawn.
The rejection of claim 8 under 35 U.S.C. 112(d) is withdrawn as moot because claim 8 was cancelled.
The above rejections were overcome by Applicant’s amendments to the claims
Claim Rejections – 35 USC § 112(d) – Previously Presented
The following is a quotation of 35 U.S.C. 112(d):
“(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.”
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
“Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.”
The rejection of claims 11-12 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends is maintained.
Response to Arguments
The Applicant submitted that the amendments to claims 11-12 obviate the rejection but give any reasoning for this conclusion. Claims 11 and 12 still fail to further limit the subject matter of the claims upon which they depend because they recite inherent properties of the composition of claim 1. They do not further limit the ingredients or form of the composition.
Reiterated Rejection
Claims 11 and 12 recite:
The pharmaceutical composition of claim 1, wherein the polysorbate degradation is reduced relative to a pharmaceutical composition comprising histidine chloride as the histidine buffer salt.
Claim 11;
The pharmaceutical composition of claim 11, wherein the polysorbate ester hydrolysis is reduced relative to a pharmaceutical composition comprising histidine chloride as the histidine buffer salt.
Claim 12.
These claims merely recite inherent properties of the pharmaceutical composition of claim 1. As stated in the specification, “The solutions comprising histidine malate (MAL), histidine maleate (MALE), histidine fumarate (FUM), histidine tartrate (TAR), histidine citrate (CIT), histidine phosphate (FOS) or histidine lactate (LAK) showed no significant degradation of polysorbate 80” (Specification, p. 18). Claims 11 and 12 fail to further limit the subject matter of claim 1 because they are directed towards the properties of the composition without further limiting the structure or form of the composition.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections – 35 USC § 102 – Previously Presented
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.”
The rejection of claims 1-12 and 16-20 under 35 U.S.C. 102(a)(1) based upon a public use or sale or other public availability of the invention. The claimed invention was on sale as the product TAKHZYRO as evidenced by the FDA label for TAKHYZRO dated November 2018 (herein “the FDA label”) is maintained.
The rejection of claims 1-12 and 16-20 under 35 U.S.C. 102(a)(1) as being anticipated by Jezek et al. (US20190262450A1) is maintained.
Response to Arguments
The Applicant argues that TAKHZYRO does not contain histidine citrate and histidine phosphate because TAKHZYRO teaches that the stabilized pharmaceutical composition contains L-histidine, citric acid monohydrate and sodium phosphate dibasic dihydrate (Remarks, p. 6). These arguments were fully considered but are not persuasive. An aqueous solution containing L-histidine and citric acid will necessarily contain histidine citrate in the form of dissolved ions or an ion pair. This is identical to a solution containing histidine citrate. The histidine citrate refers to the ionic interaction of the two substances in solution, which will necessarily be present as dissolved ions.
The Applicant argues that the formulation includes L-histidine monohydrochloride and that Jezek is silent as to the histidine buffer salt is not histidine chloride or histidine acetate (Remarks, p. 6). These arguments were fully considered but are not persuasive. Jezek teaches a complete solution comprising 20 mg/mL or 180 mg/ml tocilizumab, L- histidine (21 mM), L-arginine (100 mM) , L-lactic acid (10 mM), sodium chloride (10 mM), polysorbate 80 (0.2 mg/mL), and water for injection, pH 6.0 (Jezek, Specification, ¶ 0172). This solution does list L-histidine monohydrochloride as stated by the Applicant. While the Applicant argues that Jezek does not explicitly teach the negative limitation, “Novelty is not created by a negative limitation where one skilled in the art would have read the prior art reference to exclude the relevant step.” Innovatit Seafood Systmes, LLC v. Comm'r For Patients, 573 F. Supp. 2d 96, 100 (D.D.C. 2008). Jezek teaches a formulation without histidine chloride or histidine acetate. Therefore, the claims remain anticipated.
Reiterated Rejection
Claims 1-7, 9-12 and 16-20 are rejected under 35 U.S.C. 102(a)(1) based upon a public use or sale or other public availability of the invention. The claimed invention was on sale as the product TAKHZYRO as evidenced by the FDA label for TAKHYZRO dated November 2018 (herein “the FDA label”).
Claim 1 is directed towards a stabilized pharmaceutical composition comprising an active agent, polysorbate, and a histidine buffer consisting of histidine and a histidine buffer salt, wherein the histidine buffer salt is selected from the group consisting of histidine malate, histidine maleate, histidine fumarate, histidine tartrate, histidine citrate, histidine phosphate, histidine lactate, and mixtures thereof.
TAKHYZRO is a stabilized pharmaceutical composition comprising an active agent, polysorbate, and a histidine buffer consisting of histidine and a histidine buffer salt, wherein the histidine buffer salt is histidine citrate and histidine phosphate:
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FDA label, p. 6.
Therefore, claim 1 is anticipated.
Claim 2 is directed towards the pharmaceutical composition of claim 1, wherein the polysorbate is selected from the group consisting of polysorbate 20, polysorbate 21, polysorbate 40, polysorbate 60, polysorbate 61, polysorbate 65, polysorbate 80, polysorbate 81, polysorbate 85, polysorbate 120, and mixtures thereof.
As shown on page 6 of the FDA label above, TAKHYZRO contains polysorbate 80.
Therefore, claim 2 is anticipated.
Claim 3 is directed towards the stabilized pharmaceutical composition of claim 1, comprising the polysorbate in a concentration of from about 0.0001% (w/v) to about 1.0% (w/v). Claim 16 is directed towards the stabilized pharmaceutical composition of claim 3 comprising the polysorbate in a concentration of from about 0.01% (w/v) to about 0.25% (w/v).
As shown on page 6 of the FDA label above, TAKHYZRO contains polysorbate 80 at a concentration of 0.1 mg/mL which is 0.01% (w/v).
Therefore, claims 3 and 16 are anticipated.
Claim 4 is directed towards the stabilized pharmaceutical composition of claim 1, comprising the histidine buffer salt in a concentration of from about 1 mM to about 200 mM. Claim 17 is directed towards the stabilized pharmaceutical composition of claim 4, comprising the histidine buffer salt in a concentration of from about 5 mM to about 100 mM. Claim 18 is directed towards the stabilized pharmaceutical composition of claim 4, comprising the histidine buffer salt in a concentration of from about 10 mM to about 50 mM.
As shown on page 6 of the FDA label above, TAKHYZRO contains 7.8 mg/mL of L-histidine which is about 50 mM, 4.1 mg/mL of citric acid monohydrate which is about 20 mM, and 5.3 mg/mL of sodium phosphate dibasic dihydrate which is about 30 mM. Thus, the concentration of the histidine buffer salt is about 50 mM.
Therefore, claims 4, 17 and 18 are anticipated.
Claim 5 is directed towards the stabilized pharmaceutical composition of claim 1, wherein the pH of the composition is from about pH 4.0 to about pH 8.5. Claim 19 is directed towards the stabilized pharmaceutical composition of claim 5, wherein the pH of the composition is from about pH 5.5 to about pH 7.0.
As shown on page 6 of the FDA label above, the pH of TAKHYZRO is 6.0.
Therefore, claims 5 and 19 are anticipated.
Claim 6 is directed towards the pharmaceutical composition of claim 1, wherein the composition comprises a therapeutically effective amount of the active agent. Claim 7 is directed towards the stabilized pharmaceutical composition of claim 1, wherein the active agent is a protein. Claim 20 is directed towards the stabilized pharmaceutical composition of claim 7, wherein the active agent is a monoclonal or a polyclonal antibody, or an antigen-binding fragment thereof.
TAKHZYRO is an FDA approved product “indicated for prophylaxis to prevent attacks of hereditary angioedema (HAE) in patients 12 years and older.” (FDA label, p. 2). The active ingredient in TAKHZYRO is Lanadelumab-flyo, “a fully human monoclonal antibody (IgG1/κ-light chain) that binds plasma kallikrein and inhibits its proteolytic activity.” (FDA label, p. 6). “The efficacy of TAKHZYRO for the prevention of angioedema attacks in patients 12 years of age and older with Type I or II HAE was demonstrated in a multicenter, randomized, double-blind, placebo-controlled parallel-group study” (FDA label, p. 8).
Therefore, claims 6-7 and 20 are anticipated.
Claim 9 is directed towards the stabilized pharmaceutical composition of claim 1, wherein the composition is a liquid composition or a lyophilized composition. Claim 10 is directed towards the stabilized pharmaceutical composition of claim 1, for intravenous, subcutaneous or intramuscular administration.
As shown on page 6 of the FDA label above, TAKHZYRO is a liquid solution for subcutaneous use.
Therefore, claims 9-10 are anticipated.
Claims 11 and 12 recite:
The pharmaceutical composition of claim 1, wherein the polysorbate degradation is reduced relative to a pharmaceutical composition comprising histidine chloride as the histidine buffer salt.
Claim 11;
The pharmaceutical composition of claim 11, wherein the polysorbate ester hydrolysis is reduced relative to a pharmaceutical composition comprising histidine chloride as the histidine buffer salt.
Claim 12.
These claims merely recite inherent properties of the pharmaceutical composition of claim 1. As such, they are anticipated by the product TAKHZYRO, which is identical to the claimed invention.
Claims 1-7, 9-12 and 16-20 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Jezek et al. (US20190262450A1).
Claim 1 is directed towards a stabilized pharmaceutical composition comprising an active agent, polysorbate, and a histidine buffer consisting of histidine and a histidine buffer salt, wherein the histidine buffer salt is selected from the group consisting of histidine malate, histidine maleate, histidine fumarate, histidine tartrate, histidine citrate, histidine phosphate, histidine lactate, and mixtures thereof.
Jezek provides: “a liquid pharmaceutical composition comprising tocilizumab (an anti-IL-6R antibody), a histidine buffer and a stabilizer selected from lactic acid or salts thereof. Said composition further comprises a free amino acid, a surfactant and optionally a salt.” (Jezek, Specification, ¶ 0008).
Jezek teaches an exemplary stabilized pharmaceutical formulation comprising 20 mg/mL or 180 mg/ml tocilizumab, L- histidine (21 mM), L-arginine (100 mM) , L-lactic acid (10 mM), sodium chloride (10 mM), polysorbate 80 (0.2 mg/mL), and water for injection, pH 6.0 (Jezek, Specification, ¶ 0172). As such the formulation comprises an active ingredient (tocilizumab), a histidine buffer consisting of histidine and a histidine buffer salt (L-histidine and histidine lactate), and a polysorbate (polysorbate 80).
Therefore, claim 1 is anticipated.
Claim 2 is directed towards the pharmaceutical composition of claim 1, wherein the polysorbate is selected from the group consisting of polysorbate 20, polysorbate 21, polysorbate 40, polysorbate 60, polysorbate 61, polysorbate 65, polysorbate 80, polysorbate 81, polysorbate 85, polysorbate 120, and mixtures thereof.
As shown above, Jezek teaches that the formulation contains polysorbate 80. Jezek also teaches other polysorbates such as polysorbate 20:
Preferred surfactants are polysorbates, such as polysorbate 20 (alternative name: polyoxyethylene (20) sorbitan monolaurate), polysorbate 40 (alternative name: polyoxyethylene (20) sorbitan monopalmitate), polysorbate 60 (alternative name: polyoxyethylene (20) sorbitan monostearate) or polysorbate 80 (alternative name: polyoxyethylene (20) sorbitan monooleate, or Tween 80®).
Jezek, Specification, ¶ 0050.
Therefore, claim 2 is anticipated.
Claim 3 is directed towards the stabilized pharmaceutical composition of claim 1, comprising the polysorbate in a concentration of from about 0.0001% (w/v) to about 1.0% (w/v). Claim 16 is directed towards the stabilized pharmaceutical composition of claim 3 comprising the polysorbate in a concentration of from about 0.01% (w/v) to about 0.25% (w/v).
As shown in the rejection of claim 1, Jezek teaches 0.2 mg/mL of polysorbate, which is 0.02% (w/v).
Therefore, claims 3 and 16 are anticipated.
Claim 4 is directed towards the stabilized pharmaceutical composition of claim 1, comprising the histidine buffer salt in a concentration of from about 1 mM to about 200 mM. Claim 17 is directed towards the stabilized pharmaceutical composition of claim 4, comprising the histidine buffer salt in a concentration of from about 5 mM to about 100 mM. Claim 18 is directed towards the stabilized pharmaceutical composition of claim 4, comprising the histidine buffer salt in a concentration of from about 10 mM to about 50 mM.
As shown in the rejection of claim 1, Jezek teaches 21 mM of L-histidine and 10 mM of lactic acid. As such, the formulation comprises about 10 mM of histidine lactate.
Therefore, claims 4, 17 and 18 are anticipated.
Claim 5 is directed towards the stabilized pharmaceutical composition of claim 1, wherein the pH of the composition is from about pH 4.0 to about pH 8.5. Claim 19 is directed towards the stabilized pharmaceutical composition of claim 5, wherein the pH of the composition is from about pH 5.5 to about pH 7.0.
As shown in the rejection of claim 1, Jezek teaches that the pH of the formulation is 6.0.
Therefore, claims 5 and 19 are anticipated.
Claim 6 is directed towards the pharmaceutical composition of claim 1, wherein the composition comprises a therapeutically effective amount of the active agent. Claim 7 is directed towards the stabilized pharmaceutical composition of claim 1, wherein the active agent is a protein. Claim 20 is directed towards the stabilized pharmaceutical composition of claim 7, wherein the active agent is a monoclonal or a polyclonal antibody, or an antigen-binding fragment thereof.
Jezek teaches that the formulation comprises 20 mg/mL or 180 mg/mL of tocilizumab, a pharmaceutically effective amount as this is the amount present in the commercial formulation for intraveneous or subcuteneous administration, ACTEMRA (Jezek, Specification, ¶¶ 0003-4). Tocilizumab is an anti-IL-6R antibody (id., ¶ 0008). “The term “antibody”, and its plural form “antibodies”, as used herein includes, inter alia, polyclonal antibodies, affinity-purified polyclonal antibodies, monoclonal antibodies, and antigen-binding fragments.” (id., ¶ 0017).
Therefore, claims 6-7 and 20 are anticipated.
Claim 9 is directed towards the stabilized pharmaceutical composition of claim 1, wherein the composition is a liquid composition or a lyophilized composition. Claim 10 is directed towards the stabilized pharmaceutical composition of claim 1, for intravenous, subcutaneous or intramuscular administration.
Jezek teaches that the pharmaceutical formulation is a liquid for subcutaneous administration or intravenous administration (Jezek, Specification, ¶¶ 0170-172).
Therefore, claims 9-10 are anticipated.
Claims 11 and 12 recite:
The pharmaceutical composition of claim 1, wherein the polysorbate degradation is reduced relative to a pharmaceutical composition comprising histidine chloride as the histidine buffer salt.
Claim 11;
The pharmaceutical composition of claim 11, wherein the polysorbate ester hydrolysis is reduced relative to a pharmaceutical composition comprising histidine chloride as the histidine buffer salt.
Claim 12.
These claims merely recite inherent properties of the pharmaceutical composition of claim 1. As such, they are anticipated by the formulation of Jezek, which is identical to the claimed invention.
Claim Rejections - 35 USC § 103 – Previously Presented
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.
The rejection of claims 1-7, 9-12 and 16-20 under 35 U.S.C. 103 as being unpatentable over Jezek et al. (US20190262450A1), as applied to claims 1-12 and 16-20 above, and further in view of Sek (European Pharmaceutical Review, 10 July 2012, Issue 3 2012, p. 1-10) is maintained
Response to Arguments
The Applicant argues that a skilled artisan would have no motivation or reasonable expectation of success to substitute malic acid for lactic acid because Sek teaches that lactic acid buffers are suitable substitutes for acetate and citrate (Remarks, p. 7). These arguments were fully considered but are not persuasive. One of ordinary skill in the art would have a reasonable expectation of success to substitute malic acid for lactic acid in a liquid pharmaceutical formulation for injection because it is one of a finite number of accepted buffers for this purpose. The disclosure of preferred buffers or substitutions does not undermine the reasonable expectation of success. “Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971)” (MPEP § 2123.II).
Reiterated Rejection
Claims 1-12 and 16-20 are rejected under 35 U.S.C. 103 as being unpatentable over Jezek et al. (US20190262450A1), as applied to claims 1-12 and 16-20 above, and further in view of Sek (European Pharmaceutical Review, 10 July 2012, Issue 3 2012, p. 1-10).
In response to a Restriction/ Election requirement mailed June 17, 2025, the Application elected histidine malate as the species for examination if no generic claim was allowable (Remarks, p. 5-6). Sek is cited to address the species histidine malate.
As shown above, Jezek teaches a pharmaceutical formulation comprising histidine buffer (histidine and histidine lactate). While Jezek does not teach histidine malate, one of ordinary skill in the art would have a reasonable expectation of success to substitute malic acid for lactic acid in a liquid pharmaceutical formulation for injection because it is one of a finite number of accepted buffers for this purpose.
For example, Sek teaches that there are only about 14 buffers used in parenteral products including malic acid:
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Sek, p. 2.
Sek teaches that the most common buffers found in parenteral formulations have been citrate, phosphate and acetate (Sek, p. 2). Sek teaches that it will become necessary to test less commonly used buffers to provide adequate stability (id.). Thus, malic acid is one of a small number of identified buffers for use in parenteral products and would be obvious to try with a reasonable expectation of success.
As such, the invention as a whole was prima facie obvious at the time of filing.
Conclusion
No claim is found to be allowable.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to HEATHER DAHLIN whose telephone number is (571)270-0436. The examiner can normally be reached 9-5.
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/HEATHER DAHLIN/Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
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