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 .
Claims 1-20 have been presented for examination on the merits.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Suggestion: claim 18 is directed to a method for preventing or treating thrombotic disease comprising administering to a subject in need thereof a composition comprising as an active ingredient, the pharmaceutical formulation of claim 10.
The claim is hard to read and follow because “a composition comprising a formulation” is vague. Typically, compositions are formulations, and as such it is not clear how a composition comprises a formulation. Also, “as an active ingredient, the pharmaceutical formulation” is inaccurate because a formulation is not an active ingredient rather it comprises an active ingredient.
Furthermore, “thrombotic disease” is inaccurate. It should either be a thrombotic disease or thrombotic diseases.
Objection to Specification
The Specification is objected to for reciting trademarks such as PolysorbateTM 40, PolysorbateTM 60 and PolysorbateTM 80, without including their proprietary nature of the marks. Although the use of trademarks having definite meanings is permissible in patent applications, the proprietary nature of the marks should be respected. Trademarks should be identified by capitalizing each letter of the mark (in the case of word or letter marks) or otherwise indicating the description of the mark (in the case of marks in the form of a symbol or device or other nontextual form). Every effort should be made to prevent their use in any manner which might adversely affect their validity as trademarks.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 18-20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The specification, while being enabling for treating thrombotic diseases with administration of the formulation of claim 10, does not reasonably provide enablement for prevention of such diseases. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
To be enabling, the specification of the patent must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1561 (Fed. Cir. 1993).
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth by In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Formal, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors:
1) the quantity of experimentation necessary,
2) the amount of direction or guidance provided,
3) the presence or absence of working examples,
4) the nature of the invention,
5) the state of the prior art,
6) the relative skill of those in the art,
7) the predictability of the art, and
8) the breadth of the claims.
The nature of the invention, relative skill level, and breadth of the claims
The instant invention is directed to methods of preventing or treating thrombotic disease comprising administering to a subject in need thereof a composition comprising as an active ingredient, the pharmaceutical formulation of claim 10.
The complex nature of the claims is greatly exacerbated by the breath of the claims. The claims encompass broad ways that a composition comprising the plasma protein ADAMTS13 and one or more amino acids can prevent a thrombotic disses. The relative skill of those in the art is high, that of an MD or PHD.
The state and predictability of the art
The state of the art recognizes that protein ADAMTS13 and one or more amino acids stabilizers are effective in treating thrombotic diseases. As illustrative of the state of the art, the examiner cites Soejima (US 20120064057).
The lack of significant guidance from the specification or the prior art with regard to preventing thrombotic diseases makes practicing the scope of the invention unpredictable. Prevention as defined by medical dictionary means: “Action so as to avoid, forestall, or circumvent a happening, conclusion, or phenomenon (for example, disease prevention)” (see http://medical-dictionary.thefreedictionary.com/prevention). And ‘to prevent’ means: “To keep from happening” (see http://www.thefreedictionary.com/prevent).
The claim is thus very broad insofar as it recites prevention of thrombotic diseases, i.e., to keep from happening. While such “prevention” might theoretically be possible under strictly controlled laboratory conditions, as a practical matter it is nearly impossible to achieve in the “real world” in which patients live; thrombotic disease are always a risk.
The amount of direction or guidance provided and the presence or
absence of working examples
The specification provides no direction or guidance for preventing thrombotic diseases. Due to the vastness of these diseases and their causes one of ordinary skill would undergo undue experimentation in deducing if the formulation actually prevents any and all thrombotic diseases within applicant’s scope.
The specification does not provide any working examples of preventing or treating thrombotic diseases.
The quantity of experimentation necessary
Because of the known unpredictability of the art, and in the absence of experimental evidence, no one skilled in the art would accept the assertion that the instantly claimed formulation could be predictably used to prevent any thrombotic disease as inferred by the claim and contemplated by the specification. Accordingly, the instant claims do not comply with the enablement requirement of §112, since to practice the invention claimed in the patent a person of ordinary skill in the art would have to engage in undue experimentation, with no assurance of success.
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.
Claims 1-20 are 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.
Claims 1-20 are indefinite because claims 1 and 5 recite a concentration range for the amino acid stabilizer or the inorganic salt in mM without indicating its base. That is, it is not clear if the said mM is based on 1 mL or 1L or else. Remaining claims are indefinite for depending on rejected claim 1.
Claim 9 is indefinite for reciting PolysorbateTM 40, PolysorbateTM 60 and PolysorbateTM 80. When a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirement of 35 U.S.C. 112, second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. See MPEP § 608.01(v).
Applicant’s claims
Claim 1 is directed to a pharmaceutical formulation comprising 0.2 mg/ml to 1.2 mg/ml of plasma protein and 40 mM to 200 mM of amino acid stabilizer.
Claim 10 is directed to the formulation of claim 1, wherein the protein is ADAMTS 13.
Claim 18 is directed to a method for treatment of a thrombotic disease by administration of the composition of claim 10 to a subject.
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.
(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.
Claims 1-4 and 8-9 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Allan et al (US 20100254985).
Allan et al teach formulations of proteins comprising a variant Fc region that improve the stability in part by reducing the propensisty of such molecules to rapidly aggregate (See abstract).
Regarding claims 1, 3 and 8, Allan et al teach a liquid formulation comprising an Fc variant protein, a buffering agent at a concentration between 1 mM to 100 mM and further comprising one or more component selected from the group consisting of: (a) a carbohydrate excipient at a concentration between 1% to 20% weight to volume; (b) a cationic amino acid at a concentration between 1 mM to 400 mM; (c) an anion at a concentration between 1 mM to 200 mM; and (d) a polysorbate at a concentration between 0.001% to 0.1%. The said formulations comprise an Fc variant protein at about 1 mg/mL (See [0013], [0215] and claim 1).
Regarding claim 2, Allan et al teach the liquid formulation wherein the cationic amino acid is lysine, arginine or histidine (See [0014], [0074] and claim 8).
Regarding claim 4, Allan et al teach the said carbohydrate excipient is trehalose, sucrose, etc, (See [0014], [0073] and claim 7).
Regarding claims 8-9, Allan et al teach that the polysorbate is selected from the group consisting of polysorbate-40 (Tween 40), polysorbate-60, and polysorbate-80 (See [0078], embodiment 51 [0275] and claim 19).
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.
Claims 1-10, 18-20 are rejected under 35 U.S.C. 103 as being unpatentable over Allan et al (US 20100254985) in combination with Matthiessen et al (US 20190247475).
Allan et al teach formulations of proteins comprising a variant Fc region that improve the stability in part by reducing the propensisty of such molecules to rapidly aggregate (See abstract).
Regarding claims 1, 3 and 8, Allan et al teach a liquid formulation comprising an Fc variant protein, a buffering agent at a concentration between 1 mM to 100 mM and further comprising one or more component selected from the group consisting of: (a) a carbohydrate excipient at a concentration between 1% to 20% weight to volume; (b) a cationic amino acid at a concentration between 1 mM to 400 mM; (c) an anion at a concentration between 1 mM to 200 mM; and (d) a polysorbate at a concentration between 0.001% to 0.1%. The said formulations comprise an Fc variant protein at about 1 mg/mL (See [0013], [0215] and claim 1).
Regarding claim 2, Allan et al teach the liquid formulation wherein the cationic amino acid is lysine, arginine or histidine (See [0014], [0074] and claim 8).
Regarding claim 4, Allan et al teach the said carbohydrate excipient is trehalose, sucrose, etc, (See [0014], [0073] and claim 7).
Regarding claims 8-9, Allan et al teach that the polysorbate is selected from the group consisting of PolysorbateTM 40 (Tween 40), PolysorbateTM 60, PolysorbateTM 80 (See [0078], embodiment 51 [0275] and claim 19).
Regarding claims 5-7, Allan et al teach that the said formulations may comprise agents for the adjustment of tonicity, such as sodium chloride and dextrose (See [0220]).
Regarding claims 18-20, in part, Allan et al teach that the said formulations are effective in treating diseases and conditions including idiopathic thrombocytopenia purpura (ITP) (See [0208]).
Allan et al is silent with regard to the addition of calcium chloride or the amount of the inorganic salt or the protein being ADAMTS13. These are known in the art as taught by Matthiessen et al.
Matthiessen et al teach liquid and lyophilized formulations of ADAMTS13 that are suitable for pharmaceutical administration useful for the treatment of various diseases and conditions (See abstract).
Regarding claims 1 and 5-7, Matthiessen et al teach a formulation comprising 0.05 mg/ml to 10.0 mg/ml ADAMTS13; 0 mM to 100 mM of a pharmaceutically acceptable salt, 0.5 mM to 20 mM calcium; a sugar and a nonionic surfactant (See [0016]-[0018] and claim 1). The salt is preferably sodium chloride and is present at between 0 mM and 200 mM or between 0 and 90 mM (See [0098]-[0099] and Claim 23). The said calcium may be a calcium chloride and is present at between 0.5 to 20 mM. The composition may comprise two or more tonicity agents including sodium chloride and calcium chloride (See [0104] and [0108]).
Regarding claims 8-9, Matthiessen et al teach that the said formulation comprises between about 0.01% and 0.1% of a nonionic surfactant, wherein the surfactant is selected from the group consisting of PolysorbateTM 20, PolysorbateTM 80 (See [0102] and [0117]).
Regarding claim 10, Matthiessen et al teach that the protein is ADAMTS13 (See entire disclosure).
Regarding claims 18-20, Matthiessen et al teach that the said formulations are suitable for treatment of thrombotic diseases and conditions, including thrombotic thrombocytopenic purpura (TTP), a disorder characterized by thrombotic microangiopathy; acquired TTP, arterial thrombosis, acute myocardial infarction (AMI), stroke, sepsis, and disseminated intravascular coagulation (DIC). The method comprises administering to a subject in need thereof a therapeutically effective dose of an ADAMTS13 formulation, such as A13 or rA13 formulation (See at least [0021], [0237] and claim 21).
It would have been prima facie obvious to a person of ordinary skilled in the art at the time the invention was made to have combined the teachings of Matthiessen et al with that of Allan et al to arrive at the instant invention with a reasonable expectation of success. It would have been obvious to do so because both references teach formulations comprising a protein and additives including amino acids to effectively treat thrombocytopenia purpura in a subject. The difference is that Allan et al do not teach wherein the said protein is ADAMTS 13. However this is well known in the art as taught by Matthiessen et al, which teach formulations comprising ADAMTS 13 as a suitable and effective protein. Thus, it would have been obvious to one of ordinary skill in the art to have incorporated Matthiessen et al’s protein, ADAMTS 13 into the formulations of Allan et al to prepare a formulation or another formulation that is effective in treating thrombosis related conditions such as thrombocytopenia purpura in a subject.
The claims would have been obvious because a person of ordinary skill has good reasons to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense.
Claims 1-4, 8-20 are rejected under 35 U.S.C. 103 as being unpatentable over Allan et al (US 20100254985) in combination with Soejima (8,685,665).
Allan et al’s teachings are delineated above and incorporated herein.
Allan et al is silent with regard to the protein being ADAMTS13 or its substitutions, it’s use in treating thrombotic diseases and the FC region substitutions. These are known in the art as taught by Soejima.
In addition to teachings and recitations as stated above, Allan et al teach the following:
Regarding claims 14-17, in part, Allan et al teach that antibodies, i.e, a protein consisting of one or more polypeptides substantially encoded by all or part of the recognized immunoglobulin genes, wherein the antibody fragments are fused to an Fc region. The immunoglobulin molecules can be of any type (e.g., IgG), class (e.g., IgG1, IgG4, etc,) or subclass of immunoglobulin molecule (See [0121] and [0135]). The said Fc region includes the polypeptides comprising the constant region of an antibody excluding the first constant region immunoglobulin domain. Thus, Fc refers to the last two constant region immunoglobulin domains and the flexible hinge N-terminal to these domains. For IgG, Fc comprises immunoglobulin domains Cgamma2 and Cgamma3 (Cγ2 and Cγ3) and the hinge between (Cγ1) and (Cγ2). Although the boundaries of the Fc region may vary, the human IgG heavy chain Fc region is usually defined to comprise residues C226 or P230 to its carboxyl-terminus (See [0100]). Further disclosed is a formulation wherein the Fc variant protein comprises at least one of the amino acid sequences selected from the group consisting of: SEQ ID NOS: 2 (See [0248], [0296] and [0210]).
Regarding claims 18-20, in part, Allan et al teach that the said formulations are effective in treating diseases and conditions including idiopathic thrombocytopenia purpura (ITP) (See [0208]).
Soejima teach a method of enhancing an enzymatic activity of a disintegrin-like domain, and metalloprotease, with an isolated human thrombospondin type 1 motif, member 13 (ADAMTS-13) by substituting one or more positions in the isolated human ADAMTS-13 (See abstract).
Regarding claims 11-13, Soejima teach a method of enhancing an enzymatic activity of ADAMTS-13 (a disintegrin-like domain, and metalloprotease, with an isolated human thrombospondin type 1 motif, member 13, the method comprising substituting the following positions in the isolated human ADAMTS-13 with a different amino acid: aspartic acid at position 287, aspartic acid at position 298, glutamic acid at position 309, arginine at position 312, lysine at position 318, glutamic acid at position 327, aspartic acid at position 340, glutamic acid at position 363, lysine at position 364, lysine at position 368, arginine at position 370, arginine at position 372, arginine at position 386, arginine at position 452, arginine at position 459, glutamic acid at position 492, lysine at position 497, aspartic acid at position 500, aspartic acid at position 504, arginine at position 514, glutamic acid at position 515, aspartic acid at position 516, arginine at position 535, aspartic acid at position 537, arginine at position 544, aspartic acid at position 551, asparagine at position 552, arginine at position 558, lysine at position 559, arginine at position 566, arginine at position 568, glutamic acid at position 569, asparagine at position 579, lysine at position 608, asparagine at position 614, arginine at position 625, arginine at position 629, glutamic acid at position 634, aspartic acid at position 635, arginine at position 636, arginine at position 639, arginine at position 644, glutamic acid at position 651, arginine at position 659, glutamic acid at position 663, glutamic acid at position 664, asparagine at position 667, arginine at position 670, or arginine at position 683 in the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:1 (See Table 1, claims 1 and 3).
Regarding claims 18-20, Soejima teach that thrombotic thrombocytopenic purpura (TTP) caused by a reduced activity of ADAMTS-13 is classified into a congenital TTP and an acquired TTP (See Col. 1, lines 57-60). A therapeutic agent for thrombotic disease comprising as an active ingredient the ADAMTS-13 mutant. The thrombotic disease is disseminated intravascular coagulation (DIC), hemolytic-uremic syndrome (HUS), deep vein thrombosis (DVT), thrombotic thrombocytopenic purpura (TTP) (See Col. 5, Lines 55-67).
It would have been prima facie obvious to a person of ordinary skilled in the art at the time the invention was made to have combined the teachings of Soejima et al with that of Allan et al to arrive at the instant invention with a reasonable expectation of success. It would have been obvious to do so because both references teach formulations comprising a protein and additives to effectively treat thrombocytopenia purpura in a subject. The difference is that Allan et al do not teach wherein the said protein is ADAMTS 13. However this is well known in the art as taught by Soejima et al, which teach formulations comprising ADAMTS 13 as a suitable and effective protein. Thus, it would have been obvious to one of ordinary skill in the art to have incorporated Soejima et al’s protein, ADAMTS 13 into the formulations of Allan et al to prepare a formulation or another formulation that is effective in treating thrombosis related conditions such as thrombocytopenia purpura in a subject.
The claims would have been obvious because a person of ordinary skill has good reasons to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense.
Claims 1-20 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Mina Haghighatian whose telephone number is (571)272-0615. The examiner can normally be reached M-F, 7-5 EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Sue X. Liu can be reached at 571-272-5539. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/Mina Haghighatian/
Mina Haghighatian
Primary Examiner
Art Unit 1616
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