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 Group I and species of 1,4,7-triazacyclononane-N,N',N"-triacetic acid (NOTA) and gallium-68 (Ga-68) in the reply filed on June 2, 2026 is acknowledged.
Claim Rejections - 35 USC § 112 Indefiniteness
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 6 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.
In claim 6, the term “contrast excipient” renders the scope of the claim vague and ambiguous. In the pharmaceutical and medical imaging arts, the terms “contrast (agent)” and “excipient” possess mutually exclusive, contradictory definitions. A “contrast agent” is universally understood as an active pharmaceutical ingredient or diagnostic substance designed to actively alter the visual contrast of tissues or fluids during medical imaging. Conversely, an “excipient” is defined as an inactive or inert substance formulated alongside an active ingredient to serve as a carrier, stabilizer, or vehicle. By concatenating theses contradictory terms into a single phrase “contrast excipient”, it is unclear to a person of ordinary skill in the arte whether the claimed “contrast excipient” is intended to function as an active imaging contrast medium in addition to the multivalent glyco-complex according to claim 1, an inactive formulation carrier that is merely used within a contrast composition, or a hybrid substance performing the dual function. A review of the specification reveals that “contrast excipient” is not a standard term of art, nor has any distinct, specialized definition been provided within the specification for the term to act as its own lexicographer. Because the boundary of what a “contrast excipient” cannot be reasonably ascertained from the disclosure, the metes and bounds of the claimed invention are indefinite.
Clarification and/or amendment is required.
For the purposes of applying art, “contrast excipient” is being interpreted as a pharmaceutically acceptable excipient or an inactive substance formulated alongside the active ingredient of a medication.
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.
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 1-6 are rejected under 35 U.S.C. 103 as being unpatentable over Lin et al. (US 10,925,981, 2021; cited on PTO-892) in view of Narayanan et al. (US 9,051,418, 2015; cited on PTO-892).
Regarding claims 1-5, Lin discloses a hexa-lactoside-NOTA derivative conjugate comprising NOTA (chelating group) and Ga-68 (radioactive nuclide) as a positron emission tomography (PET) imaging agent (abstract). Lin discloses the derivative can have a structure of
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(claim 1). Both the conjugate of Lin and the conjugate of Formula (3) of instant claims represent dendritic molecular scaffolds coordinating a radioactive nuclide complex, conjugated to sugar moieties for targeted molecular imaging. Both structures have identical chelating moieties. However, the conjugate of Lin features a hexavalent architecture displaying 6 disaccharide units (lactose) arranged in pairs at the end of each branch, linked via alkyl chains. Formula (3) of instant claim features a trivalent architecture containing 3 monosaccharide (glucose derivative) subunits, linked via polyethylene glycol (PEG) chains. Both structures utilize central nitrogen-based core composed of multi-functional amino acids like lysine, but the conjugate of Lin requires an extended, complex poly-lysine dendrimeric core to bifurcate the branches thereby doubling the valency from 3 to 6. Regarding claim 6, Lin discloses that the imaging agent can be prepared with sodium acetate buffer (claim 3; column 8, lines 59-62). It can be expected that the imaging agent comprises the radio-labeled compound and sodium acetate buffer (excipient).
Lin does not disclose the conjugate comprising trivalent glucose-PEG moiety.
Narayanan discloses a linear glucose-PEG conjugate such as glucose-PEG-BODIPY ® and glucose-PEG-OH (FIGs 1 and 2). Narayanan discloses that such glucose-PEG conjugate can carry a detectable label such as a PET label (Ga-68), and that the conjugate can be useful for the imaging of hyper-proliferative cells, such as cancer cells (column 2, lines 40-43; column 6, lines 23-33) because a high rate of glucose uptake and increased glucose metabolism are involved in maintaining that proliferation of tumor cells (column 1, lines 34-36).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the conjugate of Lin by replacing the hexavalent lactose moiety with a trivalent glucose moiety in order to prepare an effective imaging agent for cancer cells. A person of ordinary skill in the art would have been motivated to make these modifications and reasonably would have expected success because Narayanan teaches that the glucose-PEG moiety can be useful for an imaging agent for cancer cells. Specifically, A person of ordinary skill in the art would have been motivated to select a trivalent structure rather than a lower-valency or higher-valency alternative. A trivalent presentation of glucose may maximize the multivalent binding affinity to glucose transporters overexpressed on cancer cells, while strictly avoiding the excessive steric hindrance and prolonged blood circulation time typically associated with higher-valency structures, thereby achieving an optimal target-to-background ratio. A person of ordinary skill in the art would have been motivated to conjugate the PEG linker to the C-2 position of glucose (glucosamine) to ensure that the molecule is still recognized by cancer cells as glucose via glucose transporter, while utilizing an amide bond to provide in vivo stability. It would have been customary for a person of ordinary skill in the art to optimize the binding position and number of the glucose-PEG moieties in order to achieved the desired performance characteristics. The length of PEG linkers is a result-effective parameter that a person of ordinary skill in the art would routinely optimize in order to achieve the effective agent activity. Further, a person of ordinary skill in the art would have been motivated to utilize smaller trivalent monosaccharide with hydrophilic PEG linkers instead of a complex hexavalent disaccharide structure with hydrophobic alky linkers in order to achieve higher contrast imaging, rapid renal clearance, reduced steric hindrance, improved synthetic yield, and reduced cost.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-6 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 of U.S. Patent No. US 10,925,981 (cited on PTO-892) in view of Narayanan et al. (US 9,051,418, 2015; cited on PTO-892).
Regarding claims 1-5, claim 1 of the ‘981 recites a hexa-lactoside-NOTA derivative conjugate, having a structure of
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. Both the conjugate of the ‘981 and the conjugate of Formula (3) of instant claims represent dendritic molecular scaffolds coordinating a radioactive nuclide complex, conjugated to sugar moieties for targeted molecular imaging. Both structures have identical chelating moieties. However, the conjugate of the ‘981 features a hexavalent architecture displaying 6 disaccharide units (lactose) arranged in pairs at the end of each branch, linked via alkyl chains. Formula (3) of instant claim features a trivalent architecture containing 3 monosaccharide (glucose derivative) subunits, linked via polyethylene glycol (PEG) chains. Both structures utilize central nitrogen-based core composed of multi-functional amino acids like lysine, but the conjugate of the ‘981 requires an extended, complex poly-lysine dendrimeric core to bifurcate the branches thereby doubling the valency from 3 to 6.
Regarding claim 6, claim 3 of the ‘981 recites that the imaging agent can be prepared with sodium acetate buffer. The imaging agent would comprise the radio-labeled compound and sodium acetate buffer (excipient).
The claims of the ‘981 do not recite the conjugate comprising trivalent glucose-PEG moiety.
As discussed above, Narayanan discloses a linear glucose-PEG conjugate such as glucose-PEG-BODIPY ® and glucose-PEG-OH (FIGs 1 and 2). Narayanan discloses that such glucose-PEG conjugate can carry a detectable label such as a PET label (Ga-68), and that the conjugate can be useful for that imaging of hyper-proliferative cells, such as cancer cells (column 2, lines 40-43; column 6, lines 23-33) because a high rate of glucose uptake and increased glucose metabolism are involved in maintaining that proliferation of tumor cells (column 1, lines 34-36).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the conjugate of the ‘981 by replacing the hexavalent lactose moiety with a trivalent glucose moiety in order to prepare an effective imaging agent for cancer cells. A person of ordinary skill in the art would have been motivated to make these modifications and reasonably would have expected success because Narayanan teaches that the glucose-PEG moiety can be useful for an imaging agent for cancer cells. Specifically, A person of ordinary skill in the art would have been motivated to select a trivalent structure rather than a lower-valency or higher-valency alternative. A trivalent presentation of glucose may maximize the multivalent binding affinity to glucose transporters overexpressed on cancer cells, while strictly avoiding the excessive steric hindrance and prolonged blood circulation time typically associated with higher-valency structures, thereby achieving an optimal target-to-background ratio. A person of ordinary skill in the art would have been motivated to conjugate the PEG linker to the C-2 position of glucose (glucosamine) to ensure that the molecule is still recognized by cancer cells as glucose via glucose transporter, while utilizing an amide bond to provide in vivo stability. It would have been customary for a person of ordinary skill in the art to optimize the binding position and number of the glucose-PEG moieties in order to achieved the desired performance characteristics. The length of PEG linkers is a result-effective parameter that a person of ordinary skill in the art would routinely optimize in order to achieve the effective agent activity. Further, a person of ordinary skill in the art would have been motivated to utilize smaller trivalent monosaccharide with hydrophilic PEG linkers instead of a complex hexavalent disaccharide structure with hydrophobic alky linkers in order to achieve higher contrast imaging, rapid renal clearance, reduced steric hindrance, improved synthetic yield, and reduced cost.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JONG HWAN BAEK whose telephone number is (571)272-0670. The examiner can normally be reached Mon - Thu, 9 am - 3 pm ET.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Michael G 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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/JONG HWAN BAEK/Examiner, Art Unit 1618
/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618
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