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 .
Election/Restrictions
Applicant’s election without traverse of dimercaptosuccinic acid as labeling ligand and sodium potassium tartrate as exchange ligand in the reply filed on 2/24/2026 is acknowledged. Claims 1-24 are pending and are examined herein on the merits for patentability.
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 22 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. The phrase "e.g” followed by parentheses renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim 17 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. The claim contains multiple phrases in parentheses that renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d). The recitation of (DTPA, NADTPA, NaCaDTPA) appears to be a broad limitation followed by preferred embodiments of salts; further NA should be Na. In another instance, Sodium thiosulphate pentahydrate (sulfur colloid) and Stannous chloride dihydrate (tin colloid) are recited; it is unclear that the phrases in parentheses are defining or broadening the previous terms. Clarification is requested.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1, 11, 13-15, 17-18, 21, 23 and 24 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Whitehouse (US 4,229,427).
Whitehouse discloses stable compositions, useful as technetium-99m-based scintigraphic agents, comprise hydroquinone in combination with a pertechnetate reducing agent or dissolved in pertechnetate-99m solution. The compositions are especially useful in combination with a phosphate or phosphonate material which carries the radionuclide to bone, thus providing a skeletal imaging agent (abstract).
The following examples are illustrative of compositions made according to this invention. The quantity of each component listed is in milligrams.
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Each of the compositions of Examples I through X, upon addition of about 5 ml. of a pertechnetate-99m solution from a commercial technetium source, and thorough shaking, yields a skeletal scanning agent suitable for intravenous injection into a human patient (column 10-11). Accordingly, a labeling ligand, reducing agent, bulking agent and antioxidant are combined in dry form, as claimed.
Claim(s) 1, 11, 13-15, 17-21, 23 and 24 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Fawzi (US 4,232,000).
Fawzi teaches stable compositions, useful as technetium-99m-based scintigraphic agents, comprise gentisyl alcohol or a pharmaceutically-acceptable salt or ester thereof in combination with a pertechnetate reducing agent or dissolved in pertechnetate-99m solution. The compositions are especially useful in combination with a phosphate or phosphonate material which carries the radionuclide to bone, thus providing a skeletal imaging agent (abstract).
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Each of the compositions of Examples I through X, upon addition of about 5 ml. of a pertechnetate-99m solution from a commercial technetium source, and thorough shaking, yields a skeletal scanning agent suitable for intravenous injection into a human patient (column 10-11). Accordingly, a labeling ligand, reducing agent, bulking agent and antioxidant are combined in dry form, as claimed.
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.
Claim(s) 1, 3-11, 13-15, 17-18, 21, 23 and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Whitehouse (US 4,229,427).
Whitehouse discloses stable compositions, useful as technetium-99m-based scintigraphic agents, comprise hydroquinone in combination with a pertechnetate reducing agent or dissolved in pertechnetate-99m solution. The compositions are especially useful in combination with a phosphate or phosphonate material which carries the radionuclide to bone, thus providing a skeletal imaging agent (abstract).
The following examples are illustrative of compositions made according to this invention. The quantity of each component listed is in milligrams.
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media_image1.png
368
792
media_image1.png
Greyscale
Each of the compositions of Examples I through X, upon addition of about 5 ml. of a pertechnetate-99m solution from a commercial technetium source, and thorough shaking, yields a skeletal scanning agent suitable for intravenous injection into a human patient (column 10-11). Accordingly, a labeling ligand, reducing agent, bulking agent and antioxidant are combined in dry form, as claimed.
It would have been obvious to one of ordinary skill in the art at the time of the invention to modify the order of addition of components in the compositions taught by Whitehouse. One would have been motivated to do so in order to combine the ingredients in the claimed amounts, with a reasonable expectation of success in providing a stable composition. See MPEP 2144 directed to changes in sequence of adding ingredients. Ex parte Rubin, 128 USPQ 440 (Bd. App. 1959) (Prior art reference disclosing a process of making a laminated sheet wherein a base sheet is first coated with a metallic film and thereafter impregnated with a thermosetting material was held to render prima facie obvious claims directed to a process of making a laminated sheet by reversing the order of the prior art process steps.). See also In reBurhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946) (selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results); In reGibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930) (Selection of any order of mixing ingredients is prima facie obvious.).
Claim(s) 1, 3-11, 13-15, 17-21, 23 and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Fawzi (US 4,232,000).
Fawzi teaches stable compositions, useful as technetium-99m-based scintigraphic agents, comprise gentisyl alcohol or a pharmaceutically-acceptable salt or ester thereof in combination with a pertechnetate reducing agent or dissolved in pertechnetate-99m solution. The compositions are especially useful in combination with a phosphate or phosphonate material which carries the radionuclide to bone, thus providing a skeletal imaging agent (abstract).
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348
710
media_image2.png
Greyscale
Each of the compositions of Examples I through X, upon addition of about 5 ml. of a pertechnetate-99m solution from a commercial technetium source, and thorough shaking, yields a skeletal scanning agent suitable for intravenous injection into a human patient (column 10-11). Accordingly, a labeling ligand, reducing agent, bulking agent and antioxidant are combined in dry form, as claimed.
It would have been obvious to one of ordinary skill in the art at the time of the invention to modify the order of addition of components in the compositions taught by Fawzi. One would have been motivated to do so in order to combine the ingredients in the claimed amounts, with a reasonable expectation of success in providing a stable composition. See MPEP 2144 directed to changes in sequence of adding ingredients. Ex parte Rubin, 128 USPQ 440 (Bd. App. 1959) (Prior art reference disclosing a process of making a laminated sheet wherein a base sheet is first coated with a metallic film and thereafter impregnated with a thermosetting material was held to render prima facie obvious claims directed to a process of making a laminated sheet by reversing the order of the prior art process steps.). See also In reBurhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946) (selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results); In reGibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930) (Selection of any order of mixing ingredients is prima facie obvious.).
Claim(s) 1-24 are rejected under 35 U.S.C. 103 as being unpatentable over -Schiller (US 2016/0355532).
Schiller teaches a non-radioactive kit for the preparation of a radiopharmaceutical composition, comprising at least one container, wherein one container contains:
(i) a stabilized form of Tetrofosmin (i.e. labeling ligand) according to the invention.
Preferably the kit comprises one or several additional ingredients selected from:
(ii) reductant, preferably a tin(II) salt,
(iii) transfer ligand, such as gluconate and/or sulphosalicylate,
(iv) preservative,
(v) agents for pH adjustment, such as hydrogen carbonate or phosphate salts and
(vi) fillers.
Whilst components (i) to (iii) are preferably comprised in the kit, components (iv) to (vi) are optionally.
The kit preferably comprises the stabilized form of Tetrofosmin according to the invention in powder form, more preferably in a freeze-dried powder form (paragraph 0048-57). Suitable transfer ligands include tartrates. Additional preferred transfer ligands are selected from dimercaptosuccinic acid (paragraph 0068).
The agent for pH adjustment preferably comprises a member selected from the group consisting of pharmaceutically acceptable buffers or agents for pH adjustment, such as citrate, hydrogen and/or sodium carbonates, hydrogen phosphates, TRIS, tricine or mixtures thereof. A preferred agent for pH adjustment for the kits according to the invention is a salt of carbonic acid, like carbonate or hydrogen carbonate, more preferably sodium hydrogen carbonate (NaHCO3) (paragraph 0072). Preferably, agents for pH adjustment or pH regulating agents comprise sterile solutions or sterile powders of the salts (paragraph 0071).
Suitable fillers include inorganic salts such as sodium chloride, and water soluble sugars or sugar alcohols such as sucrose, maltose, D(−)-mannitol or trehalose. Certain buffer salts or agents for pH adjustment may also function as bulking agents (paragraph 0075).
The preservatives are preferably selected from the group consisting ascorbic acid, benzyl alcohol, cresol; cetrimide, thiomersal, phenol and the parabens (paragraph 0078).
Preferably, the formulation of a non-radioactive kit is produced by mixing all ingredients in an aqueous solution. The formulation may then be sterile filtered, e.g. through a sterile 0.2 μm filter. The formulation is preferably filled into sterile containers. The containers are subsequently sealed and optionally lyophilized. This is preferably performed by first partially sealing the containers, followed by lyophilization and subsequently sealing and capping (paragraph 0063).
In a particularly preferred embodiment of the invention, the non-radioactive kit comprises: 1) a first container containing: (i) a stabilized form of Tetrofosmin according to the invention, preferably the tetrafluoroborate salt of Tetrofosmin according to formula (II), (ii) a reductant, preferably a tin (II) salt, (iii) one or more transfer ligands, preferably gluconate and sulphosalicylate (iv) optionally a filler, preferably D(−)-mannitol. 2) a second container comprising: (i) a buffer or agent for pH adjustment, preferably a salt of carbonic acid, like carbonate or hydrogen carbonate, (as powder or solution).
In this case the technetium complex is preferably formed by first adding to the first container the content of the second container, thus releasing the free Tetrofosmin ligand. In case of a powdery buffer or agent for pH adjustment, a diluent comprising water, preferably water for injections or a saline solution (sterile solution of sodium chloride) is added to the second vial prior to adding the content to the first vial. Subsequently the pertechnetate solution is added to the mixture of the first and the second vial, resulting in the formation of a pharmaceutical formulation for intravenous administration (paragraph 0088-96).
A multi dose kit comprises at least one container, preferably one or two different containers. Preferably at least one container contains the stabilized form of Tetrofosmin according to the invention in a sufficient amount so that preferably 2 to 20 single unit patient doses of a radiopharmaceutical composition, comprising the 99mTc-tetrofosmin complex, can be obtained (paragraph 0109).
In Example 3, a tetrofosmin kit comprises the following composition:
0.34 mg
Tetrofosmin × 2 HBF4
0.32 mg
disodium sulfosalicylate
1.0 mg
sodium D-gluconate
20 mg
D-(−)-mannitol
0.03 mg
SnCl2 × 2 H2O
The kit is labeled in approx. 3.5 mL pertechnetate eluate with 300 MBq 99mTc at pH 4-5 and room temperature. The mixture was gently swirled until complete dissolution of the powder.
It would have been obvious to one of ordinary skill in the art at the time of the invention to provide a radiopharmaceutical cold kit without lyophilization comprising providing a labeling ligand, a reducing agent, a bulking agent and at least one of an antioxidant and an exchange ligand in dry form and combining the components to produce a dry powder mixture without the use of a lyophilization step in view of Schiller. One would have been motivated to do so, with a reasonable expectation of success, because Schiller specifically teaches that the claimed components are components of a stabilized tetrofosmin kit in powder form, and further teaches that lyophilization of the kit is an optional step. With regard to claims 3-10 directed to the order of combining the plurality of ingredients, see MPEP 2144 directed to changes in sequence of adding ingredients. Ex parte Rubin, 128 USPQ 440 (Bd. App. 1959) (Prior art reference disclosing a process of making a laminated sheet wherein a base sheet is first coated with a metallic film and thereafter impregnated with a thermosetting material was held to render prima facie obvious claims directed to a process of making a laminated sheet by reversing the order of the prior art process steps.). See also In reBurhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946) (selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results); In reGibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930) (Selection of any order of mixing ingredients is prima facie obvious.).
Conclusion
No claims are allowed at this time.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LEAH H SCHLIENTZ whose telephone number is (571)272-9928. The examiner can normally be reached Monday-Friday, 8:30am - 12:30pm EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, MICHAEL HARTLEY can be reached at 571-272-0616. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/LHS/
/Michael G. Hartley/ Supervisory Patent Examiner, Art Unit 1618
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