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 .
Summary
Claims 1-13, 15, 17, 19-22, and 24-27 are pending in this office action. Claims 14, 16, 18, and 23 are cancelled. All pending claims are under examination in this application.
Priority
The current application was filed on June 7, 2024 is a 371 of PCT/FI2022/050826 filed on December 12, 2022. The current application claims foreign priority to FI20216268 filed on December 13, 2021.
Claim Objections
Claims 2-5, 7, 10, 20, 22, and 27 are objected to because of the following informalities:
Claims 2 and 10: Please use the acronym L-BPA instead of the fully defined text.
Claim 3: Please make the first letter of the named 2HAs lowercase.
Claims 4, 10, 20, and 22: The 2HA tris(hydroxymethyl)aminomethane should be lowercase. [The acronym (Tris) is capitalized.]
Claim 5: The Applicant seemed to not include “about 1.5” after “…in the range of 1-1.5...”.
Claims 7 and 10: The Applicant has used ≥, ≤, <, ˃ or = within these limitations. Please confirm these are correct.
Claim 27: BPA is already defined within claim 1, and therefore the full text is not needed within the text.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 27 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 27 is written as a “use” claim and does not recite process steps. Additionally, claim 27 does not comply with the four statutory categories. It is therefore, indefinite.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claim 27 is directed to non-statutory subject matter. The claim does not fall within at least one of the four categories of patent eligible subject matter because it is written as a “use” claim.
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 non-obviousness.
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 1-13, 15, 17, 19-22, and 24-27 are rejected under 35 U.S.C. 103 as being unpatentable over Miyamoto et al. (JP5150084B2) in view of Zaludek et al. (WO2014/198337A1) and Beck-Sickinger et al. (WO2019/115609A1).
[The Examiner is going to introduce each reference and then combine them where appropriate to reject the instant claims.]
1. Miyamoto et al.
Miyamoto et al. is the closest prior art to the present invention as it teaches highly water-soluble p-boronophenylalanine-containing composition (see title). Additionally, Miyamoto et al. disclose the following:
PROBLEM TO BE SOLVED: To provide a method for supplying an aqueous solution having a pH in the vicinity of neutrality by dissolving p-boronophenylalanine in water in a high concentration in comparison with a conventional method and to obtain the aqueous solution obtained by the method.
SOLUTION: The medicine composition is in a form of an aqueous solution containing p-boronophenylalanine and meglumine, having a meglumine content to p-boronophenyl-alanine of at least 0.8 in a molar ratio and a pH in the vicinity of neutrality or in a form of a dried material for providing an aqueous solution having a pH in the vicinity of neutrality (see abstract).
2. Zaludek et al.
Zaludek et al. teach stable and water-soluble pharmaceutical compositions comprising pemetrexed (see title). In addition, Zaludek et al. disclose that the present invention relates to a solid pharmaceutical composition comprising pemetrexed and a solubilizing amount of meglumine or tromethamine. The composition is sufficiently stable for purpose of making pharmaceutical formulations, particularly lyophilized formulations, and is sufficiently soluble in water for purposes of using in parenteral administration (see abstract).
3. Beck-Sickinger et al.
Beck-Sickinger et al. teach saccharide functionalised carbaborane conjugates of human peptide y (see title). Furthermore, Beck-Sickinger et al. disclose that the present invention covers peptidic human Y1 receptor agonist - saccharide functionalised carbaborane conjugate compounds of general formula (I): X5PSX 1PX6FPGX7X8X9PX10X11X12X13X2X14YYX3X15X16X17X4YINLITRPRY-NH2, in which F, G, I, L, N, P, R, S, T, Y, X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, X14, X15, X16, and X17 are as described and defined herein, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds, and the use of said compounds for manufacturing pharmaceutical compositions for the treatment of cancer by means of boron neutron capture therapy (see abstract).
Combination of Miyamoto et al. and Zaludek et al.
Regarding instant claim 1, Miyamoto et al. and Zaludek et al. teach a pharmaceutical composition comprising boronophenylalanine (BPA) or a pharmaceutically acceptable salt thereof and a 2-hydroxy amine compound (2HA) or a pharmaceutically acceptable salt thereof. The necessary citations within Miyamoto et al. and Zaludek et al. that pertain to instant claim 1 are presented in Table I.
Table I
Instant Claim 1
Miyamoto et al. and Zaludek et al. Citations
A pharmaceutical composition comprising boronophenylalanine (BPA) or a pharmaceutically acceptable salt thereof and a 2-hydroxy amine compound (2HA) or a pharmaceutically acceptable salt thereof, wherein the 2HA is selected from the compounds set forth in any one of the formulas I to II or a pharmaceutically acceptable salt thereof, or any combination or mixture thereof:
Miyamoto et al. disclose boron-containing compositions with increased water solubility for use as a boron source in boron neutron capture therapy (see title, abstract, and claims; all within Miyamoto et al.). In particular, the medicine composition disclosed is in a form of an aqueous solution containing p-boronophenyl-alanine and meglumine, having a meglumine content to p-boronophenyl-alanine of at least 0.8 in a molar ratio and a pH in the vicinity of neutrality or in a form of a dried material for providing an aqueous solution having a pH in the vicinity of neutrality (see Example 1 within Miyamoto et al.). Miyamoto et al. disclose a method for producing a p-boronophenylalanine containing composition, which further comprises the step of lyophilizing the p-boronophenylalanine containing aqueous solution (see claim 15 within Miyamoto et al.). Furthermore, the pharmaceutical composition is useful as an agent for boron neutron capture therapies in treatment of tumors (see paragraphs [0014] and [0047] within Miyamoto et al.).
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Zaludek et al. disclose a solid pharmaceutical composition comprising pemetrexed and a solubilizing amount of meglumine or tromethamine (see claim 1; and page 5, lines 1-17 within Zaludek et al.) (see the structure of tromethamine below).
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The composition is sufficiently stable for the purpose of making pharmaceutical formulations, particularly lyophilized formulations, and is sufficiently soluble in water for purposes of use in parenteral administration (see page 9, lines 9-15 within Zaludek et al.).
The feature described in Zaludek et al. provides the same advantages as the addition of Formula (I) or Formula (II) to the composition in the present application. The skilled person would therefore regard it as a normal option to replace the solubilizing agent from Miyamoto et al. (2-hydroxy amine: meglumine) with an alternative solubilizing agent from Zaludek et al. (2-hydroxy amine: tromethamine) in order to solve the problem posed.
It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify Miyamoto et al. with the teachings of Zaludek et al. to insert by simple substitution of meglumine the 2-hydroxyamine compound tromethamine disclosed by Zaludek et al. The motivation for doing so would have been to expand the polyols, such as meglumine, to include 2HA agents.
Regarding instant claim 2, Miyamoto et al. and Zaludek et al. teach wherein the BPA is L-p-boronophenylalanine or a pharmaceutically acceptable salt thereof.
Miyamoto et al. disclose a pharmaceutical composition according to any one of claims 1 to 8, wherein p-boronophenylalanine is L-p-boronophenylalanine (see claim 9 within Miyamoto et al.).
Regarding instant claims 5 and 21, Miyamoto et al. and Zaludek et al. teach wherein the molar ratio of 2HA:BPA is in the range of 0.5-3, about 0.5, in the range of 0.5-1, about 1, in the range of 1-1.5, in the range of 1-2, about 2, in the range of 2-3, or about 3.
Miyamoto et al. disclose a molar ratio of the solubilizing agent, meglumine (2HA) to BPA of 0.8 to 2.5 (see claims 1-3 within Miyamoto et al.). [The Examiner established the 35 U.S.C. §103 rejection, where there is a simple substitution of the polyol, meglumine, with the tromethamine as disclosed by Zaludek et al.]
Regarding instant claim 6, Miyamoto et al. and Zaludek et al. teach wherein the pharmaceutical composition further comprises a polyol, and the molar proportions and/or amounts of the BPA, the 2HA, and the polyol are such that the sum of the molar amounts of BPA and polyol is about equal to or larger than the molar amount of BPA.
Miyamoto et al. disclose Comparative Example 1 (see paragraph [0025] within Miyamoto et al.) wherein BPA (30 g) and fructose (66.7 g) are added together. Furthermore, Example 1 (see paragraph [0026] within Miyamoto et al.) mixes BPA (30 g) and meglumine (42.2 g) together. Combination of the two yields:
BPA 30 g; 209.01 g/mol; 144 mmol (BPA is used in a 30 g amount for both Examples).
Fructose 66.7 g; 180.16 g/mol; 370 mmol
Meglumine (equiv. to 2HA) 42.2 g; 195.21 g/mol; 216 mmol
(144 mmol BPA + 370 mmol fructose) ≥ 144 mmol BPA.
Regarding instant claim 7, Miyamoto et al. and Zaludek et al. teach wherein the pharmaceutical composition further comprises a polyol, and the molar proportions and/or amounts of the BPA, the 2HA, and the polyol are such that [2HA] + [polyol] ≤ 4.0 x [BPA]; [216 mmol meglumine + 370 mmol fructose ≤ 4.0 x 144 mmol BPA].
Regarding instant claim 8, Miyamoto et al. and Zaludek et al. teach wherein the pharmaceutical composition further comprises at least one of hydrochloric acid, sodium chloride, acetic acid, sodium acetate, polyethylene glycol, a polyol, a saccharide, fructose, mannitol or sorbitol.
Miyamoto et al. disclose the addition of hydrochloric acid to adjust the pH (see paragraph [0021] within Miyamoto et al.) to a value of 6-8 (see claims 7 and 10 within Miyamoto et al.).
Regarding instant claims 11 and 12, Miyamoto et al. and Zaludek et al. teach wherein the pharmaceutical composition is an aqueous solution, and wherein the aqueous solution optionally has a pH in the range of 6.5 to 8.5.
Miyamoto et al. disclose the pharmaceutical composition according to claim 6, which, when restored by adding water, gives an aqueous solution with a pH of 6.0 to 8.0 (see claims 7 and 10 within Miyamoto et al.).
Regarding instant claim 13, Miyamoto et al. and Zaludek et al. teach wherein the concentration of BPA in the aqueous solution is at least 30 g/L.
Miyamoto et al. disclose a method for producing the aqueous solution according to any one of claims 10 to 13, wherein the concentration of p-boronophenylalanine in the aqueous solution is at least 3 w/v% (3 w/v% x 10 = 30 g/L) (see claim 14 within Miyamoto et al.).
Regarding instant claims 15 and 24, Miyamoto et al. and Zaludek et al. teach wherein the pharmaceutical composition is a dry formulation, wherein the dry formulation is optionally capable of forming an aqueous solution having a pH in the range of 6.5 to 8.5 upon addition of water.
Miyamoto et al. disclose a method for producing a p-boronophenylalanine-containing composition, which further comprises the step of lyophilizing the p-boronophenylalanine containing aqueous solution (see claim 15; and paragraph [0023]; both within Miyamoto et al.). Additionally, please see instant claims 11 and 12 regarding the pH of the pharmaceutical composition.
Regarding instant claim 17, Miyamoto et al. and Zaludek et al. teach wherein the BPA has at least 30 %, at least 40 %, at least 50 %, at least 60 %, at least 70 %, at least 80 %, at least 90 %, at least 95 %, at least 97 %, at least 98 %, or at least 99 % boron-10 atoms of all boron atoms in the BPA.
Miyamoto et al. disclose the BPA used below was synthesized by conventional methods using boron in which the ratio of NER10 B to total boron was concentrated from approximately 20% in nature to 95% (manufactured by Stella Chemifa Co., Ltd.). However, since the mass number of boron does not affect the chemical properties, the results obtained in the examples apply to BPA containing NER11 B in any ratio (see paragraph [0024] within Miyamoto et al.).
Regarding instant claim 19, Miyamoto et al. and Zaludek et al. teach a method for preparing the pharmaceutical composition according to instant claim 1, the method comprising mixing BPA with the 2HA to form an aqueous solution of the BPA and the 2HA, optionally mixing a polyol with the BPA and the 2HA or adding a polyol to the aqueous solution, and adjusting the pH of the aqueous solution to a pH in the range of 6.5 to 8.5.
Miyamoto et al. disclose the preparation of BPA and meglumine (equivalent to 2HA) within Example 1 (see paragraph [0026]; also see claim 4 regarding a pH of 6.0 to 8.0; both within Miyamoto et al.) which follows the instant claim 19 protocol.
Regarding instant claim 25, Miyamoto et al. and Zaludek et al. teach wherein the method comprises providing the pharmaceutical composition as a dry formulation, and mixing the pharmaceutical composition as the dry formulation with water and optionally with one or more compounds selected from hydrochloric acid, sodium chloride, acetic acid, sodium acetate, polyethylene glycol, a polyol, a saccharide, fructose, mannitol and sorbitol, thereby obtaining the pharmaceutical composition as an aqueous solution.
Please see the discussion and citations within instant claims 1, 8, 15, and 24 for the necessary rejection text.
Regarding instant claim 26, Miyamoto et al. and Zaludek et al. teach wherein the concentration of the BPA in the aqueous solution is in the range of 30-120 g/L, and the pH of the aqueous solution is about pH 7.4, or a physiological pH or a substantially physiological pH.
Please see the discussion and citations within instant claims 1, 13, 15, and 24 for the necessary rejection text.
Regarding instant claim 27, Miyamoto et al. and Zaludek et al. teach the use of a 2-hydroxy amine compound (2HA) or a pharmaceutically acceptable salt thereof as defined within instant claim 1 in dissolving boronophenylalanine (BPA) or a pharmaceutically acceptable salt thereof, thereby forming a pharmaceutical composition comprising BPA as an aqueous solution.
Please see the discussion and citations within instant claim 1 for the necessary rejection text.
Combination of Miyamoto et al., Zaludek et al., and Beck-Sickinger et al.
Beck-Sickinger et al. synthesizes compounds used in boron neutron capture therapy, similar to BPA (see title, abstract, background, and claims within Beck-Sickinger et al.). Several solubilizing salts are used to promote their pharmacokinetic properties (see pages 44-45 within Beck-Sickinger et al.). Therefore, making this reference analogous art.
Regarding instant claims 3-4, Miyamoto et al., Zaludek et al., and Beck-Sickinger et al. teach wherein the 2HA comprises or is tris(hydroxymethyl)aminomethane (Tris) or a pharmaceutically acceptable salt thereof.
Beck-Sickinger et al. disclose the use of tris(hydroxymethyl)aminomethane as a 2HA complex (see page 44, line 34 within Beck-Sickinger et al.).
Regarding instant claim 9, Miyamoto et al., Zaludek et al., and Beck-Sickinger et al. teach wherein the pharmaceutical composition further comprises a polyol, wherein the polyol is mannitol.
Beck-Sickinger et al. disclose the use of the polyol mannitol (see page 148, line 32 within Beck-Sickinger et al.).
Regarding instant claim 10, Miyamoto et al., Zaludek et al., and Beck-Sickinger et al. teach wherein the pharmaceutical composition comprises L-p-boronophenyl-alanine, tris(hydroxymethyl)aminomethane (Tris), and mannitol, and wherein the molar amounts of the L-p-boronophenylalanine, Tris(hydroxymethyl)aminomethane and mannitol are such that [Tris] + [mannitol] > [L-p-boronophenylalanine].
Despite the fact that none of the prior art of record specifically teaches this limitation, a skilled artisan (POSITA; person of ordinary skill in the art) would have little problem meeting this constraint. If at least 1 equivalent of Tris is used with the BPA, then any additional mannitol will be greater than the BPA alone.
Regarding instant claim 20, Miyamoto et al., Zaludek et al., and Beck-Sickinger et al. teach the method comprising mixing L-p-boronophenylalanine and tris(hydroxymethyl)aminomethane (Tris), to form an aqueous solution, mixing mannitol with the BPA and the 2HA or adding mannitol to the aqueous solution, optionally adding an agent for adjusting the pH, such as an alkali, to the aqueous solution to completely dissolve the BPA, and adjusting the pH of the aqueous solution with an acid to a pH of about pH 7.4 or a physiological pH or a substantially physiological pH.
Please see the discussion and citations within instant claims 3-4 and 19 for the necessary rejection text. Substitution of the Tris for the 2HA or adding mannitol as needed would be straightforward for a skilled artisan (POSITA).
Regarding instant claim 22, Miyamoto et al., Zaludek et al., and Beck-Sickinger et al. teach wherein the molar ratio of tris(hydroxymethyl)aminomethane (Tris):L-p- boronophenylalanine is in the range of 0.5-3, about 0.5, in the range of 0.5-1, about 1, in the range of 1-1.5, in the range of 1-2, about 2, in the range of 2-3, or about 3.
Please see the discussion and citations within instant claims 3-5 and 21 for the necessary rejection text. Substitution of the Tris for the 2HA would be straightforward for a skilled artisan (POSITA).
Analogous Art
The Miyamoto et al., Zaludek et al., and Beck-Sickinger et al. references are directed to the same field of endeavor as the instant claims, that is, a pharmaceutical composition comprising boronophenylalanine (BPA) or a pharmaceutically acceptable salt thereof and a 2-hydroxy amine compound (2HA) or a pharmaceutically acceptable salt thereof, as disclosed within instant claim 1.
Obviousness Analysis
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the BPA pharmaceutical composition disclosed by Miyamoto et al., using the teachings of Zaludek et al. and Beck-Sickinger et al. in order to arrive at the subject matter of the instant claims.
The Miyamoto et al., Zaludek et al., and Beck-Sickinger et al. references all have considerable overlap in the use of solubilizing agents. In this instance, Miyamoto et al. supplies the template for the BPA pharmaceutical composition using the solubilizing agent, meglumine, Zaludek et al. supplies the support for the 2HA compound, tromethamine, while Beck-Sickinger et al. supplies the support for the 2HA compound, Tris. All references are directed to solubilizing agents and therefore constitute analogous art under MPEP §2141.01(a). A POSITA would have reasonably consulted the three references when seeking to develop a BPA pharmaceutical composition with an enhanced solubilizing agent.
Given these teachings, a POSITA would have been motivated to combine the template for the BPA pharmaceutical composition using meglumine as disclosed by Miyamoto et al., and the support for the 2HA agents disclosed by Zaludek et al. and Beck-Sickinger et al.
The modification constitutes a simple substitution of one known element for another to obtain a predictable result [MPEP §2143(I)(B)].
The combination represents the use of a known technique to improve a similar composition in the same way [MPEP §2143(I)(C)].
The art provides a finite number of identified, predictable solutions, and the POSITA would have pursued the claimed configuration with a reasonable expectation of success [MPEP §2143(I)(E); KSR].
The combination of the BPA pharmaceutical composition using meglumine taught by Miyamoto et al. along with the use of the necessary claim limitations taught by by Zaludek et al. and Beck-Sickinger et al. would allow a research and development scientist (POSITA) to develop the invention taught in the instant application.
Furthermore, the additional claim limitations taught by both Zaludek et al. and Beck-Sickinger et al. would have been viewed by a POSITA as routine design optimizations or known modifications for solubilizing drug candidates. The motivation for doing so would have been to expand the polyols, such as meglumine, to include 2HA agents. Implementing these features in Miyamoto et al.’s BPA pharmaceutical composition would not require more than ordinary skill or routine experimentation.
Accordingly, the combination of Miyamoto et al., Zaludek et al., and Beck-Sickinger et al. provides all the elements of the claimed invention. The resulting BPA pharmaceutical composition comprising 2HA, constitutes no more than the predictable outcome of combining familiar prior art components, and therefore the claimed subject matter would have been obvious to a POSITA prior to the effective filing date of the invention.
Conclusion
No claims are allowed.
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/JOHN W LIPPERT III/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615
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