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 and Previous Objections/Rejections Status
Claims 12,17,18 and 21-25 are pending in the application. Claims 15 and 16 are cancelled in the amendment filed 7/2/26.
Any objections and/or rejections from previous office actions that have not been reiterated in this office action are obviated.
Terminal Disclaimer
The terminal disclaimer electronically filed 7/2/26 was approved on 7/2/26.
Response to Arguments
Applicant's arguments filed 7/2/26 have been fully considered but they are not persuasive.
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.
Claim(s) 12,17,18 and 21-25 is/are rejected under 35 U.S.C. 103 as being unpatentable over ThermoFisher Scientific DyLight®800, free acid certificate of analysis 2/24/12 and DyLightTM dyes, Free acid safety data sheet (10/9/14 and version:1 9/10) in view of Kovar et al. (US 7,597,878B2), Bogyo et al. (US 2018/0002375A1) and Hillman (US 2009/0252682A1) and in further view of Marshall et al. (Mol. Imaging Biol. 2010, 12:583-594) and Ra et al. (J. Invest. Derm. 2011, 131, 1061-1066) as stated in the office action mailed 4/3/26.
Applicant asserts that the Office has not provided a basis for the selection of the claimed dye for providing the claimed injectable unit dosage form. The mere existence of the compound is insufficient to render the claimed injectable unit dosage form containing the same as obvious.
The instant claims are not drawn to a method of administering an injectable formulation to a subject but are drawn to the NIR fluorescent dye
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in a dose of 0.10 mg to 0.8 mg/kg.
The Examiner asserts that DyLight®800 free acid was known dye in the art before the effective filing date of the claimed invention.
The reference of Bogyo et al. explicitly states that DyLight 800 is an infrared dye that is particularly suited for in vivo imaging applications.
It would have been obvious to one of ordinary skill in the art to select and formulate the
DyLight®800 free acid of the prior art into a container/vial comprising an injectable dose of 0.10 mg to
0.8 mg/kg. The DyLight®800 free acid injectable dose does not require actual administration into a subject. The DyLight®800 free acid was known in the art before the effective filing date of the claimed invention for in vivo imaging applications and it is known in the art to add a drug/compound into a container/vial to prepare, store and/or transport a dosage form.
The DyLight®800 free acid of the prior art encompasses the NIR fluorescent dye
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of the instant claims, has the same properties and is capable of the same functions, such as being formulated into an injectable unit dosage form and is particularly suited for in vivo imaging applications, as stated by Bogyo et al.
Products of identical chemical composition can not have mutually exclusive properties. A
chemical composition and its properties are inseparable. Thus, the claiming of a new use, new function
or unknown property which is inherently present in the prior art does not necessarily make the claim patentable and does not render the old composition patentably new to the discoverer. In re Best, 562
F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977).
Applicant asserts that Kovar et al. does not present any data relating to the safety of the disclosed core structure, only the generic disclosure cited by the Office. Here again, the Office is reminded that cyanine dyes, even those that may have analogous core structures to that of DyLight®800, do not necessarily share the same safety and toxicity profiles. Specifically, the Office is reminded of Compound 47 in U.S. Patent No. 7,488,468 in the name of Miwa et al. (hereinafter "Miwa"), which was previously cited by the Examiner as having an analogous core structure to DyLight®800. In the Amendment dated March 26, 2020, Applicant provided the Examiner with comparative toxicological studies of the free acid form of DyLight®800 and Miwa's compound 47, and these comparative toxicological studies are described in the Declarations under 37 C.F.R. § 1.132 by Dr. Alex Lyubimov and Dr. Marta Hamilton, both of which were previously submitted with the March 26, 2020 Amendment. In the studies, the PK parameters clearly show that Compound 47 is not suitable as an imaging agent - the exposure levels are too high and the elimination rate is too long. As explained in the previously submitted Rule 132 Declarations by Dr. Alex Lyubimov and Dr. Marta Hamilton, imaging agents are not optimally resident in patients for long periods after the imaging procedure and long half-lives are not desired. Both experts agreed that those skilled in the art do not want the half-life of an imaging agent to be so long that it persists in the body longer than is required for the procedure. Thus, any allegation that dye compound having an analogous structure to that of DyLight®800 free acid is "non-toxic" is misplaced and overreaching. It should be noted that IRDye 800CW carboxylate is Compound 47 of Miwa, which even at "low doses," i.e., within the ranges of 0.5-20 mg/kg or 0.05-8 mg/kg, IRDye 800CW carboxylate (or Compound 47) was determined to be too toxic for use as a pharmaceutical grade imaging agent.
The reference of Miwa is not used in the instant rejection.
The comparison of the compound of 47 of Miwa to the IS-001 of the instant claims is not a comparison of the closest prior art and merely compares one single NIR dye to the NIR dye IS-001 of the instant claims. The declaration filed previously on March 26, 2020 does not provide a comparison of the closest prior art and does not provide any data for other NIR dye compounds having analogous core structures.
The reference of Kovar et al. was used to teach the cyanine NIR dye compounds
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have an analogous core structure to that of the IS-001
instant claims, are nontoxic to a subject and are capable of being formulated in a nontoxic composition in a sterile aqueous solution and administered within the concentrations of use.
The reference of Bogyo et al. explicitly states that DyLight 800 is an infrared dye that is particularly suited for in vivo imaging applications.
Therefore, it would have been obvious to one of ordinary skill in the art that the DyLight®800 can be formulated as an injectable composition for in vivo use that is non-toxic when administered within the concentrations of use with a reasonable expectation of success. Also, any compound is toxic if administered in large doses and therefore a practitioner would administer DyLight®800 in the lowest dose and gradually increase the dosage to determine the most efficacious dose without causing harm to a subject.
Applicant asserts that Bogyo et al. teaches that NIR fluorophores, such as IRDye 800CW and DyLight series dyes, such as DyLight®800, are disclosed in the context of inclusion as part of a detectable element, D, onto the compounds
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. Accordingly, Bogyo et al. does not teach or suggest that NIR fluorophores, such as DyLight®800 alone can or should be safely used as an injectable unit dosage form for visualization of tissue of a human patient as claimed here. Bogyo et al. does not point one of skill in the art to select any unconjugated dye, let alone the specifically claimed dye, for use alone in a formulation.
The reference of Bogyo et al. does teach of conjugating DyLight®800 to the compound above but also explicitly states that DyLight 800 is an infrared dye that is particularly suited for in vivo imaging applications.
Therefore, it would have been obvious to one of ordinary skill in the that DyLight®800 can be
safely used as an injectable unit dosage form for visualization of tissue of a human patient with a
reasonable expectation of success.
Applicant asserts that Hillman only use ICG and Dextran Texas Red dye, where the sole reference to DyLight dyes is in paragraphs [0043] and [0044]: At best, Hillman directs one of skill in the art to use ICG, which is not the compound claimed. As to any alleged reasonable expectation of success purported by the Office based on Hillman, this generic disclosure cannot reasonably be relied upon to allege that any of the listed dyes - including quantum dot agents, IRDye 800, DyLight dyes, Alexa dyes, porphyrin-related dyes, cyanine dyes, active dyes such as pH-sensitive dyes, voltage sensitive dyes, calcium sensitive dyes, dyes which incorporate fluorescent (or Forster) resonance energy transfer properties, dyes with fluorescence or phosphorescence lifetime contrast - would all have any reasonable expectation of success.
The reference of Hillman explicitly teaches that DyLight dyes, IRDye800, etc. are used as optical contrast substances that can be injected into a subject. Although DyLight dyes are listed in a list of optical contrast agents that does not diminish the fact that DyLight dyes may be injected into a subject safely with a reasonable expectation of success.
Applicant asserts that Marshall et al. and Ra et al. merely teach that IRDye 800CW carboxylate and DyLight®800 can be used as fluorescent labels in conjugates and do not support the formulation of the unconjugated dye alone as an injectable unit dosage form. Marshall et al. is a toxicity study aimed at NIR dye IRDye 800CW for use in conjugates administered for NIR fluorescence molecular imaging in humans. Even if Marshall et al. provides a toxicity study of IRDye 800CW carboxylate dye at dose levels of 1, 5, and 20 mg/kg, the submitted Rule 132 Declarations showed that even those dose levels were too toxic for use alone as a pharmaceutical grade imaging agent.
The reference of Marshall et al. was not used to teach of the dose levels of 1, 5, and 20 mg/kg but was used to teach that any agent used in human clinical investigation must undergo rigorous toxicity testing.
The toxicity study of IRDye 800CW carboxylate dye at dose levels of 1, 5, and 20 mg/kg are not a
comparison to the dosages of the instant claims and are not commensurate in scope with the dosages of the instant claims that are 0.10, 0.20, 0.30, 0.35, 0.10, 0.20, 0.40, 0.45, 0.50, 0.55, 0.60, 0.65, 0.70, 0.75 or 0.8 mg/kg.
Applicant asserts that the claimed dye is not inherently a sterile injectable formulation for intravenous administration at the claimed dosage ranges for visualizing tissue in a human, nor is it obvious to select any cyanine dye, or other dye having a certificate of analysis or safety data sheet that notes a purity profile and is "stable to transport," and formulate that dye for administration to a human for visualizing tissue.
The DyLight®800 free acid certificate of analysis or safety data sheet were not used to teach of a sterile injectable formulation for intravenous administration at the claimed dosage ranges for visualizing tissue in a human.
The reference of Kovar et al. was used to teach the cyanine NIR dye compounds
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have an analogous core structure to that of the IS-001 instant claims, are nontoxic to a subject and are capable of being formulated in a nontoxic composition in a sterile aqueous solution and administered within the concentrations of use.
The reference of Bogyo et al. explicitly states that DyLight 800 is an infrared dye that is particularly suited for in vivo imaging applications.
It would have been obvious to one of ordinary skill in the art to formulate the DyLight®800 free acid of the prior art into a container/vial comprising an injectable dose of 0.10 mg to 0.8 mg/kg. The DyLight®800 free acid injectable dose does not require actual administration into a subject. The DyLight®800 free acid was known in the art before the effective filing date of the claimed invention and it is known in the art to add a drug/compound into a container/vial to prepare, store and/or transport a dosage form.
Therefore, it would have been obvious to one of ordinary skill in the art that the DyLight®800 can be formulated as an injectable composition for in vivo use that is non-toxic when administered within the concentrations of use with a reasonable expectation of success. Also, any compound is toxic if administered in large doses and therefore a practitioner would administer DyLight®800 in the lowest dose and gradually increase the dosage to determine the most efficacious dose without causing harm to a subject.
The DyLight®800 free acid of the prior art encompasses the NIR fluorescent dye
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of the instant claims, has the same properties and is capable of the same functions, such as being formulated into an injectable unit dosage form and is particularly suited for in vivo imaging applications, as stated by Bogyo et al.
Products of identical chemical composition can not have mutually exclusive properties. A
chemical composition and its properties are inseparable. Thus, the claiming of a new use, new function
or unknown property which is inherently present in the prior art does not necessarily make the claim patentable and does not render the old composition patentably new to the discoverer. In re Best, 562
F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977).
Conclusion
No claims are allowed at this time.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MELISSA JEAN PERREIRA whose telephone number is (571)272-1354. The examiner can normally be reached M9-3, T9-3, W9-3, Th9-2, F9-2.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
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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/MELISSA J PERREIRA/Examiner, Art Unit 1618
/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618
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