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 .
DETAILED ACTION
This Office Action is in response to Applicants’ Amendment and Remarks filed on 8/4/2026 in which claim 4 is amended. No claims are newly added or canceled.
Claims 1-15 are pending in the instant application and are examined on the merits herein.
Priority
The instant application claims foreign priority to IT 102022000022113 filed on 10/26/2022. Acknowledgment is made of applicant's claim for foreign priority under 35 U.S.C. 119(a)-(d). The certified copy has been filed in the instant application on 12/7/2023.
Claim Interpretation
Applicant has amended claim 4 to recite, “…wherein R₇ is Dye in at most 50 of the N-positions of formula (I)”. This amendment clarifies the scope of claim 4. The scope of claim 4 encompasses the following: Given the degree of polymerization range of 220-11200 and the limitation that at most 50 of the N-positions may be dye; 1) the degree of dye substitution is at maximum 0.45%, when DP=11200 and 2) the degree of substitution is at maximum 22%, when DP=200. Note that because the claim recites “at most 50” any value less or equal to 50 is within the scope of the claim.
Maintained Rejections
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 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 of this title, 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.
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.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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 and 4-14 are rejected under 35 U.S.C. 103 as being unpatentable over Srinivasan et al. (J. Photochem. Photobio. B, 2013, IDS), in view of Frangioni et al. (US 2016/0263249A1, used as equiv. to WO 2015/066290A1, IDS).
Srinivasan et al. discloses a chitosan-IR820 conjugate, with chitosan (85% deacetylation, 100-300 kDa (i.e. approximately 450-1350 repeat units)), for cancer cell imaging, where the conjugate has the following structure, further where the IR820 is bound to chitosan with a degree of substitution at 0.96% and the conjugate has peak absorbance at 652 nm: (Figure 1; Abstract; Sec. 3.2-3.3)
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273
370
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Srinivasan does not teach a conjugate having the linker with the structure “D” as claimed.
Frangioni et al. discloses near-infrared fluorescent dyes of Formula (I) and Formula (II): (¶0111, 0113)
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167
331
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183
368
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,
where Z is H, halogen, CN, R6, OR6, SR6, NHR6 or CH2R6, in which R6 is optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted heteroaryl, alkyl-N3, aryl- N3, aryl-halogen. Frangioni exemplifies the following dye and (PEG-NH2)-dye conjugate: (¶0148)
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289
410
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319
429
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Frangioni further discloses that: 1) The dye conjugate may be a component of a pharmaceutical composition with one or more pharmaceutically acceptable carriers, diluents, adjuvant or excipients (¶0154); 2) The compounds of the invention accumulate in a lumen or other cavity in the body, thus highlighting the lumen’s anatomical location and/or quantifying flow of the compound within the lumen. For example…blood vessels after intravenous injection of a compound or the thoracic duct after injection into the lower body (¶0019); and 3) The compounds of the invention for use in stem cell imaging have primary or secondary amines as part of their structure, which permit covalent fixation in place after treatment with paraformaldehyde (Mannich reaction) or other amine-reactive fixatives. (¶0378)
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention that Srinivasan could be modified to prepare near-infrared dye-chitosan conjugates using any of the dyes disclosed by Frangioni, provided that the linker “Z” of Frangioni terminated in a carboxyl group, thereby arriving at the instant invention. The core dye structures of Srinivasan and Frangioni are similar and both references are directed to using the dye conjugates for in vivo imaging applications, thus it is reasonable that any dye known to be useful for imaging, having a similar core structure to that of Srinivasan, would be expected to be equivalently employed in the dye-chitosan conjugate of Srinivasan. Moreover, one would find it reasonable that the dyes with linkers terminating in carboxyl groups, such as those exemplified by Frangioni, would be compatible with the chemistry of Srinivasan, because the linking chemistry of Srinivasan occurs due to a carboxyl group of the dye linker forming an amide bond with the amine groups of chitosan, analogous to the amide formed in Frangioni with the aminated PEG.
With respect to claims 13 and 14, the imaging method of Frangioni is considered to meet the limitation of imaging a glycosamine-containing structure. The instant specification defines “glycosamine-containing structure” as including blood vessels including vascular networks of capillaries of a mammal, preferably kidney vasculature. (p. 16, Ln. 6-9) Thus, because Frangioni teaches that the dye conjugates may be used to image blood vessels, Frangioni necessarily meets the limitation of imaging a “glycosamine-containing structure” when considering the scope of the claims in light of the specification.
Accordingly, the instant claims are prima facie obvious over the teachings of the prior art.
Response to Arguments
Applicants’ response with respect to the obviousness rejection over Srinivasan/ Frangioni, has been fully considered but is not persuasive.
Applicant argues that the combined prior art does not teach chitosan linked to a dye by a linkage within the scope of instantly claimed structures Q and D. Applicant states, “Claim 1's D moiety has a carbonyl group adjacent to where the D moiety is bonded to the linker Q.” Applicants’ argument is not persuasive because the statement regarding bond connectivity is incorrect and inconsistent with the instant working examples. All the working examples show bond connectivity where the carbonyl group, of the linker D, is adjacent to where D connects to chitosan, due to the carboxyl group of D forming an amide bond with the amine of chitosan. There are no working examples where the carbonyl group of D is adjacent to where D connects to Q. The chemical moieties adjacent to where D connects to Q, in the working examples, are variable and are exemplified as amine, amide, ether and aryl.
The combined prior art of Srinivasan/ Frangioni shows that the framework of a conjugate having the general structure CHITOSAN-LINKER-DYE, is known. It is well-established in the art of conjugates that linkers are meant to be modular, where provided the terminal groups of the linker can be predictably connected to both the carrier and the active agent, any linker is reasonably expected to perform the same function. Thus, any linking group disclosed by Frangioni that is within the scope of the chemical structures depicted by instant D and Q, may be substituted for the linking group of Srinivasan, in order to operatively connect chitosan (the carrier) to dye (the active agent), thereby arriving at the instant invention. Frangioni exemplifies numerous dye derivatives, as tabulated below, where the linker moiety is within the scope of the structures depicted by instant D and Q.
Compound
Page #
Compound
Page #
A71
198
WuA110
229
TG42
199
P700H
248
WuA71
218
P700SO3
249
WuA108
222
P800H
249
TG44
226
P800SO3
249
WuA38
228
L800-1C
272
Any one of these exemplifications by Frangioni could be used as a basis to modify Srinivasan to form a dye-linker-chitosan conjugate where the linker connects to chitosan via an amide bond.
The rejection is still deemed proper and is maintained.
Claims 2 and 3 are rejected under 35 U.S.C. 103 as being unpatentable over Srinivasan et al. (J. Photochem. Photobio. B, 2013, IDS), in view of Frangioni et al. (US 2016/0263249A1, used as equiv. to WO 2015/066290A1, IDS), further in view of Hung et al. (US 2002/0177577A1, reference of record).
The disclosure of Srinivasan and Frangioni are referenced as discussed above. The combined prior art does not the percentage of O-acetylation or N-acetylation in the chitosan.
Hung et al. discloses preparation of deacetylated chitosan where O-acetylation ranges from 12.3-48.8% and N-acetylation (100-DD) ranges from 16.0-52.6%. (Table 8-10; ¶0130)
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention that the chitosan of Srinivasan/Frangioni could be modified to have range of acetylation percentages at N-positions and O-positions, based on the teaching of Hung et al., thereby arriving at the instant invention. Srinivasan directs one to use 85% deacetylated chitosan, thus any deacetylation method resulting in chitosan with 15% or less total acetylation could be employed with a reasonable expectation of success. The deacetylation method of Hung could be used to provide a variety of deacetylated chitosan where the total deacetylated value is further varied such that the % O-acetylation and % N-acetylation ranges as detailed by Hung.
Accordingly, the instant claims are prima facie obvious over the teachings of the prior art.
Response to Arguments
Applicant argues that the combined prior art does not render the independent claims prima facie obvious for the reasons outlined above, thus the rejection of dependent claims that reply on the teachings of said combined prior art, should be withdrawn. Applicants' arguments are not persuasive because the rejection of the independent claims is maintained as prima facie obvious over said combined prior art, as per the response to arguments above.
The rejection is still deemed proper and is maintained.
Claim 15 is rejected under 35 U.S.C. 103 as being unpatentable over Srinivasan et al. (J. Photochem. Photobio. B, 2013, IDS), in view of Frangioni et al. (US 2016/0263249A1, used as equiv. to WO 2015/066290A1, IDS), further in view of He et al. (US 2020/0378969A1, reference of record).
The disclosure of Srinivasan and Frangioni are referenced as discussed above. The combined prior art does not teach a kit as claimed.
He et al. discloses a kit for cellular imaging comprising a dye, a wash buffer and a cell fixing solution. (Claim 1)
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention that Srinivasan/Frangioni could be modified to prepare a kit comprising the chitosan-dye conjugates, a fixative and a wash buffer, thereby arriving at the instant invention. Frangioni teaches that the dye conjugates therein may be used with a fixative for use in imaging applications. This teaching, combined with the known use of kits for biological imaging, as taught by He et al., motivates one to formulate a kit comprising the key components of Srinivasan/Frangioni because the grouping together of various objects or compositions directed to a common purpose (i.e. forming a kit) when all the individual objects or compositions are prima facie obvious. The idea of preparing a kit based on a prima facie obvious composition flows logically from the perspective of providing organization, convenience and quality control.
Accordingly, the instant claims are prima facie obvious over the teachings of the prior art.
Response to Arguments
Applicant argues that the combined prior art does not render the independent claims prima facie obvious for the reasons outlined above, thus the rejection of dependent claims that reply on the teachings of said combined prior art, should be withdrawn. Applicants' arguments are not persuasive because the rejection of the independent claims is maintained as prima facie obvious over said combined prior art, as per the response to arguments above.
The rejection is still deemed proper and is maintained.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new and/or modified ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 extension fee 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.
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Any inquiry concerning this communication or earlier communications from the examiner should be directed to DALE R MILLER whose telephone number is (571) 272-6146. The examiner can normally be reached on M-F 7:00 AM – 3:30 PM EST.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Scarlett Goon can be reached on (571) 270-5341. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/DALE R MILLER/Primary Examiner, Art Unit 1693
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