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 .
Acknowledgments and Claim Status
The Examiner acknowledges receipt of the amendment filed 9/7/2023 wherein the specification and claims 1-13 were amended and claims 14-19 were added.
Note(s): Claims 1-19 are pending.
Priority and Priority Document
This application is a 371 of PCT/EP2022/056443 filed 3/14/2022 which claims benefit to EPO EP21305322.6 filed 3/17/2021.
The Examiner acknowledges receipt of certified copies of papers required by 37 CFR 1.55 filed 9/7/2023.
Note(s): The earliest effective filing date is 3/17/2021 because the pending invention is fully supported in EP21305322.6.
Claim Interpretation
Independent claim 1 is directed to an aqueous composition comprising (a) indocyanine green and (b) a compound selected from ascorbic acid, ascorbic acid salts, and mixtures thereof
wherein a weight ratio of said compound to indocyanine green ranges from 0.15 to 15 and wherein a concentration of the indocyanine green in the aqueous composition is between 0.1 mg/ml to 30 mg/ml.
Claim 12 is directed to a kit comprising at least one lyophilized powder of the composition of claim 1 and an aqueous diluent wherein components of the kit are in separate containers.
Claim 13 is directed to a kit comprising indocyanine green and an aqueous solution comprising a compound.
Applicant’s Election
Applicant's election with traverse of Group I (pending claims 1-12 and 14-19) filed 5/8/2026 is acknowledged. The traversal is on the grounds that there is no sufficient reason or examples provided to support a conclusion that the species within Groups I and II are distinct. This is found non-persuasive because the invention reads on multiple products and uses thereof. According to 37 CFR 1.475(b), Applicant is entitled to a product and process of using said product based on the claims presented for examination.
Specifically, independent claim 1 is directed to a product comprising indocyanine green and a compound selected form ascorbic acid, ascorbic acid salts, and mixtures thereof having the desired weight ratio and concentration set forth therein. The process of use of the product of independent claim 1 is the kit of claim 12.
Claim 13 is directed to a kit comprising indocyanine green and any aqueous solution comprising any compound. The phrase ‘for preparing the aqueous composition of claim 1’ is the intended use of the kit, but the actual kit is a product that comprising indocyanine green and any aqueous solution comprising a compound. Thus, claim 13 is of a different scope from the product of independent claim 1. If the claim was written as follows, “A kit comprising the composition of claim 1 wherein components of the composition are in separate containers”, then the interpretation of claim 13 would be based on the product of independent claim 1 and included in Group I. Applicant’s attention is respectfully directed to MPEP 2111.02, Section II, which is directed to preambles which recited purpose or intended use. While the claim preamble is read in the context of the entire claim, the determination of whether preamble recitations are structural limitation or mere states of purpose are evaluated. The recitation of the intended use does not result in a structural difference in the claim, so the claim is evaluated based on the components present. If Applicant would like the claim to be considered with independent claim 1, it is respectfully requested that the claim be written in a format that requires the presence of the specific composition of claim 1.
For the reasons set forth herein, the restriction requirement is still deemed proper and is therefore made FINAL.
Applicant elected the following species for initial examination: a composition comprising aqueous indocyanine green, sodium ascorbate, and sodium chloride. The search was not expanded beyond Applicant’s elected species because prior art was found which could be used to reject the claims.
Withdrawn Claims
Claim 13 is withdrawn from further consideration by the examiner, 37 CFR 1.142(b), as being drawn to a non-elected invention.
Information Disclosure Statements
The information disclosure statements filed 1/15/2026 and 9/7/2023 were considered.
112 Second Paragraph Rejections
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 10-12 and 17-19 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 10 and 17-19: The claims are ambiguous because of the phrase ‘content of indocyanine green’. Specifically, is Applicant referencing the ‘concentration’ of indocyanine green? It appears that the amount may remain the same, but the concentration may decrease over time. Thus, is Applicant’s reference to ‘content’ decrease related to the volume or concentration of indocyanine green?
Claim 11: The claim is ambiguous because it is unclear what components Applicant is incorporating to make the composition of claim 1 a medicament or diagnostic agent. No addition components are added in the claim as the composition is the same as that of independent claim 1. Thus, it is unclear what makes the composition a medicament or a diagnostic agent absent a diagnostic component.
Claim 12: The claim is ambiguous because it appears that Applicant intended to state that the kit components are in separate ‘containers’ not ‘compartments’. In addition, it is unclear is Applicant is actually intending the claim to read on a lyophilized powder of the composition of claim 1 or if one really intends the claim to read on multiple lyophilized powders of species from claim 1. If multiple species of lyophilized powders are present, is it still a single aqueous diluent or multiple diluents present?
103 Rejection
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 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.
Claims 1-12 and 14-19 are rejected under 35 U.S.C. 103 as being unpatentable over Alander et al (International Biomedical Imaging, 2012, Volume 2012, Article ID 940585, pages 1-26 in view of Hernandez et al (US 2016/0199524) in further view of Novadaq Technologies, Inc., (2015, pages 1-9, 20120701_a24348da-94f8-4c1c-aa8a-a161c01b5cef.pdf).
Independent claim 1 is directed to an aqueous composition comprising (a) indocyanine green and (b) a compound selected from ascorbic acid, ascorbic acid salts, and mixtures thereof
wherein a weight ratio of said compound to indocyanine green ranges from 0.15 to 15 and wherein a concentration of the indocyanine green in the aqueous composition is between 0.1 mg/ml to 30 mg/ml.
Claim 2 is directed to the aqueous composition of claim 1 wherein the weight ratio of compound (b) to indocyanine green (a) ranges from 0.20 to 13.
Claim 3 is directed to the aqueous composition of claim 1 wherein the compound (b) is ascorbic acid.
Claim 4 is directed to the aqueous composition of claim 1 wherein the compound (b) is a salt of ascorbic acid.
Claim 5 is directed to an aqueous composition of claim 4 wherein the compound (b) is selected from sodium ascorbate, potassium ascorbate, calcium ascorbate, magnesium ascorbate, and mixtures thereof.
Claim 6 is directed to an aqueous composition of claim 1 further comprising at least one compound (c) selected from reduced glutathione, thioglycerol, sorbitol, methionine, sodium chloride, histidine, dithiothreitol (DTT), and mixtures thereof.
Claim 7 is directed to an aqueous composition of claim 6 wherein a weight ratio of compound (c) to indocyanine green (a) ranges from 1:500 to 100:1.
Claim 8 is directed to an aqueous composition of claim 1,further comprising up to 5% weight by weight sodium iodide based on a weight of the indocyanine green (a).
Claim 9 is directed to an aqueous composition of claim 1 wherein the concentration of the indocyanine green (a) in the aqueous composition is between 1 and 25 mg/ml.
Claim 10 is directed to the aqueous composition of claim 1 wherein a content (concentration) of indocyanine green (a) in the aqueous composition prior to storage is greater than or equal to 90% and wherein the content of indocyanine green is measured as percentage area by HPLC at 240 nm.
Claim 11 is directed to the aqueous composition of claim 1 wherein the aqueous composition is a medicament or a diagnostic agent.
Claim 12 is directed to a kit comprising at least one lyophilized powder of the composition of claim 1 and an aqueous diluent wherein components of the kit are in separate containers.
Claim 14 is directed to the aqueous composition of claim 5 wherein the compound (b) is sodium ascorbate.
Claim 15 is directed to the aqueous composition of claim 7 wherein the weight ratio of compound (c) to indocyanine green (a) ranges from 1:100 to 10:1.
Claim 16 is directed to the aqueous composition of claim 15 wherein the weight ratio of compound (c) to indocyanine green (a) ranges from 1:100 to 4:1.
Claim 17 is directed to the aqueous composition of claim 1 wherein a drop in a content (concentration) of the indocyanine green in the aqueous composition measured in percentage area by HPLC at 240 nm is less than or equal to 10% when the aqueous composition is stored at ambient temperature for at least 1 month.
Claim 18 is directed to the aqueous composition in claim 17 wherein the drop in the content (concentration) of the indocyanine green in the aqueous composition measured in percentage area by HPLC at 240 nm is less than or equal to 5%, when the aqueous composition is stored at ambient temperature for at least 1 month.
Claim 19 is directed to the aqueous composition in claim 17 wherein the drop in the content (concentration) of the indocyanine green in the aqueous composition measured in percentage area by HPLC at 240 nm is less than or equal to 2%, when the aqueous composition is stored at ambient temperature for at least 1 month.
Alander et al is directed to a review of indocyanine green (ICG) fluorescent imaging in surgery (see entire document, especially, abstract; page 2, Table 1). It is disclosed that dry ICG is stable at room temperature. This is also the form of pharmaceutically available ICG. ICG is soluble in water (1 mg/mL), but not readily soluble in saline. As a result, Alander et al disclose that ICG should first be dissolved in water. In addition, Alander et al disclose that some chemicals such as sodium polyaspartate may be used to stabilized ICG in water (page 4, left and right columns, bridging paragraph).
Still, Alander et al disclose that in aqueous solutions, ICG molecules tend to aggregate which influences their optical properties. The aggregation depends on concentration and time. As a result, ICG solutions do not follow Lambert-beer’s law above 15 mg/L in plasma. The spectral stabilization is the fastest when ICG is dissolved in distilled water (page 4, right column, first complete paragraph).
Furthermore, based on the teachings of Alander et al, the following things would have been obvious to one of ordinary skill in the art prior to the effective date of the pending invention. (1) Alander et al disclose that it is known the art to dissolve ICG in water; thus, an aqueous solution comprising ICG is obvious. (2) Also, according to Alander et al, one would be motivated to incorporate a stabilizer because the document discloses that sodium polyaspartate is used to stabilize ICG in water. (3) Since ICG molecules tend to aggregate in water which alters their optical properties and the aggregation is concentration and time dependent, a skilled artisan would be motivated to: (a) modify (optimize) the concentration of the aqueous ICG containing mixture; (b) modify (optimize) the storage time of the aqueous ICG containing mixture; and (c) modify (optimize) the stabilizer and ICG ratio because of the information that Alander et al disclose on page 4, right column, first complete paragraph. According to MPEP 2144.05, Section II, where the general conditions of a clam are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. Hence, the teachings provided by Alander et al would motivate a skilled artisan to optimize concentration, ratio of ICG and the stabilizer, and storage time of the aqueous ICG containing mixture (composition).
While it would have been obvious to a skilled artisan to modify the concentration of the ICG composition, it is also noted that Alander et al disclose that typical dye concentrations used for in vivo retinal and choroidal angiography are in the range of 20-25 mg/ml of ICG applied by injection. For hepatic functions, an intravenous injection dose is calculated on the basis of 0.5 mg/kg of body weight. In cardiac output and blood volume monitoring, the total dose of dye injected should be kept below 2 mg/kg (page 5, left column, second complete paragraph). Thus, based on the teachings of Alander et al, a skilled artisan would conclude that depending upon the use of the ICG containing composition, the concentration range will change and may be optimized according to MPEP 2144.05 for the desired task including intraoperation angiography, neurosurgery, coronary surgery, vascular surgery, oncology and sentinel lymph node harvesting, lymphography, liver surgery and laparoscopy, laparoscopic cholecystectomy, reconstructive microsurgery, as well as other clinical applications which include brain imaging, hemodynamics, rheumatoid arthritis, burns and muscle perfusion (page 5, left column, second complete paragraph; page 10, right column, third complete paragraph; pages 10-11, bridging paragraph; page 11, left column, first complete paragraph; page 12, left column, first complete paragraph; page 12, right column, second complete paragraph; page 13, right column second complete paragraph; page 14, left paragraph, third and fourth paragraphs; page 14, right column, fifth and sixth paragraphs; page 15, left column, second complete paragraph; pages 15-16, bridging paragraph). Table 4 (page 7) disclose different task wherein an ICG containing composition may be utilized.
While it would have been obvious to a skilled artisan to modify the time (storage/use) of the ICG composition as discussed supra, it is also noted that Alander et al disclose that the important property of fast binding to plasma protein makes repeated intraoperational applications of ICG possible. The binding to plasma proteins does not seem to alter protein structures which is one sign of non-toxicity. It seems that ICG actually binds to the lipids of lipoprotein complexes and that the binding results in more intense fluorescence than ICG bound to free cholesterol, for example. Binding to blood proteins shifts, slowly, taking several minutes. Alander et al disclose that he emission peak is also shifted and not only is the shape of the spectra influenced by the chemical environment, but the fluorescence life-time changes (pages 4-5, bridging paragraph). Still, it is disclosed that ICG is swiftly removed from circulation of the liver (page 10, right column, second complete paragraph). Thus, based on the teachings of Alander et al, it would have been obvious to a skilled artisan to alter optimize storage time and time to obtain data from which time the ICG containing composition is administered.
In regard to claim 11 wherein the aqueous ICG containing composition is a medicament or a diagnostic agent, Alander et al disclose that ICG is used for imaging in surgery (see entire document, especially, abstract; page 2, Figure 1 and Table 1; page 3, Figure 2). Thus, a skilled artisan would recognize that the aqueous ICG containing mixture is used for medicinal and diagnostic purposes.
It would have been obvious to a skilled artisan prior to Applicant’s effective filing date to generate a kit (see claim 12) comprising a lyophilized powder and an aqueous diluent wherein the components are in separate containers for the following reasons. (1) Alander et al disclose that dry ICG is stable at room temperature and is the form of pharmaceutically available ICG. (2) In addition, Alander et al disclose that ICG is soluble in water and therefore, should be dissolved in water (page 4, left and right columns, bridging paragraph). Thus, the skilled artisan would recognize that having the ICG and water in separate container and mixing whenever an aqueous composition is necessary for medicinal/diagnostic purposes would reduce the formation of aggregates which are associated with are dependent upon concentration and storage time of the ICG containing solutions (page 4, right column, first complete paragraph).
While Alander et al renders obvious an aqueous composition comprising ICG and a stabilizer, the document does not specifically disclose ICG and ascorbic acid. Thus, Hernandez et al is made of record.
Hernandez et al is directed to the radiosensitivity of fluorophores and the used of radioprotective agents for dual modality imaging. The dual labeled molecules comprising a fluorescent probe and a radionuclide. The labeled molecules are used for detection, imaging, and/or diagnosis of diseased tissues (e.g., tumors). In a preferred embodiment, a radioprotective agent is used to decrease radiolysis of the fluorescent signal (see entire document, especially, abstract). Radioprotective agents that may be used include ascorbic acid (page 1, [0008]). The preferred fluorescent component may be indocyanine green (ICG) or IRDye 800CW (page 2, paragraph [0016]). The radionuclide may be 111In, 18F, 64Cu, or any of those listed on pages 2-3, paragraph [0017]).
Hernandez et al disclose a kit that comprises lyophilized ascorbic acid, water, and a targeting molecule (IMP485). The targeting molecule is labeled (page 40, paragraph [0477]; page 41, paragraph [04888]). In another embodiment, 5 mg/ml ascorbic acid was used in combination with 5.24 ml of deionized water (page 43, paragraphs [0510] – [0511]). Also, Hernandez et al disclose the formulation of a peptide kit. The kit comprises 20 µL (40 nmol) peptide, 20 µL (0.1 mg) ascorbic acid, and 900 µL deionized water in a 3 mL lyophilization vial (page 43, paragraph [0512] – [0513]). The radiolabeling process involved combining the lyophilized ascorbic acid and deionized water (page 43, paragraph [0518]).
Hernandez et al disclose that ascorbic acid or gentisic acid are added to radiopharmaceuticals during preparation to minimize radiolysis (page 44, paragraph [0528]). In the section that involves further optimization of the kit formulation, Hernandez et al disclose that ascorbic acid was varied in the different formulations (page 61, paragraph [0625]). It is disclosed that when ascorbic acid is not used in kits, the pH can change significantly along with the radiolabeling yield ( pages 61-62, bridging paragraph). In Example 34 (pages 65, paragraph [0672] – [0673], the effect of radioprotective agents on fluoresce emission in dual modality imaging probes is evaluated. In particular, Example 34 contains an aqueous (water based) buffered solution of fluorescence dye (IRDye800CW) evaluated in the presence of three radioprotective agents (ethanol, gentisic acid, and ascorbic acid). Here, it should be noted that it would have been obvious to a skilled artisan to replace one preferred dye with another (ICG) to generate an aqueous (water based) solution comprising ICG and ascorbic acid).
Based on the teachings of Hernandez et al alone (see Example 34 discussed supra), it would have been obvious to the skilled artisan prior to the effective filing date of the pending application to generate an aqueous solution comprising ICG and ascorbic acid. Hence, the combined teachings of Alander et al and Hernandez et al render obvious the optimizing of the concentration, ratio, and time (storage) of the components.
In regard to the HPLC percentage of ICG (fluorescent dye) and properties (claims 10 and 17-19), according to MPEP, if the compositions are physically the same, then they must have the same properties. In other words, products of identical (overlapping) chemical composition cannot have mutually exclusive properties as a chemical composition and its properties are inseparable.
In Applicant’s elected species, one elected an aqueous composition not only comprising ICG and ascorbic acid, but a third component, sodium chloride. It would have been obvious to incorporate sodium chloride in the compositions for the following reasons.
Novadaq Technologies, Inc. is directed to indocyanine green (ICG) as it is utilized in an ICG injection, powder, lyophilized, or as a solution. It is disclosed that an ICG injection is a lyophilized green powder contain 25 mg ICG with no more than 5% sodium iodide. ICG for injection is dissolved using sterile water (aqueous ICG solution) (page 1, first complete paragraph).
Novadaq Technologies, Inc. disclose that ICG is unstable in aqueous solution and must be used within six (6) hours (page 2, second complete paragraph). Thus, it would have been obvious to a skilled artisan to incorporate a stabilizer into the solution. In addition, the skilled artisan would recognize that significance of how storage and time would effect the ICG amounts (concentration) in the aqueous solution. Hence, based on the teachings of Alander et al supra and those of Novadaq Technologies, Inc., it would have been obvious to a skilled artisan prior to the effective date to optimize concentration and storage time.
In addressing dosage and administration of the ICG solution, Novadaq Technologies, Inc. disclose that under sterile conditions, the ICG for injection powder should be dissolved with sterile water and the solution should be used within six (6) hours after being prepared. In addition, it is recommended that the syringe used for injection of the dye be rinsed with a diluent. The matter of rinsing the dye syringe with distilled water may not be critical, since it is known that an amount of sodium chloride sufficient to make an isotonic solution may be added to the dye (ICG) that has been dissolved in distilled water. Hence, based on the teachings of Alander et al, Hernandez et al, and Novadaq Technologies, Inc., it would have been obvious to a skilled artisan prior to the effective date of the pending invention to incorporate sodium chloride into the ICG aqueous mixture containing ascorbic acid.
For the reasons set forth herein, the limitations of claims 1-12 and 14-19 are rendered obvious by the cited prior art.
Comments/Notes
For clarity of independent claim 1, the following claim language is respectfully suggested: An aqueous composition comprising (a) indocyanine green and (b) a compound selected from ascorbic acid, ascorbic acid salts, and mixtures thereof
wherein a weight ratio of said compound to indocyanine green ranges from 0.15 to 15 and wherein a concentration of the indocyanine green in the aqueous composition is between 0.1 mg/ml to 30 mg/ml.
For clarity of claims 10 and 17-19, it is respectfully requested that the “%” symbol absent a value in front of the symbol (see lines 4, 2, 2, and 2, respectively in claims 10 and 17-19) be replaced with “percentage” to ensure that there is no ambiguity that one did not intend to include a specific value.
Conclusion
Claims 1-12 and 14-19 are rejected and claim 13 is withdrawn.
Future Correspondences
Any inquiry concerning this communication or earlier communications from the examiner should be directed to D L Jones whose telephone number is (571)272-0617. The examiner can normally be reached M-F.
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/D. L. Jones/
Primary Patent Examiner
Art Unit 1618
September 8, 2026
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