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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 5/30/2025 has been entered.
Status of Claims
Claims 1 and 3 have been amended. Claims 1-12 and 14-20 are pending, of which claims 2, 7-10 and 15-18 are withdrawn as being directed to a non-elected invention and/or species. Claims 1, 3-6, 11, 12, 19 and 20 encompass the elected invention and/or species and are examined herein on the merits for patentability.
Response to Arguments
The examiner for your application in the USPTO has changed. Examiner Leah Schlientz can be reached at 571-272-9928.
Applicant’s arguments have been fully considered. Any rejection not reiterated herein has been withdrawn. New grounds for rejection have been set forth in view of amendment and/or newly discovered prior art references. The Examiner’s response to Applicant’s arguments is incorporated below.
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, 3-6, 11, 12, 14, 19 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Vasalatiy et al. (2008 Bioconjugate Chem. 19: 598-606; "Vasalatiy") in view of Deri et al. (from IDS; 2013 Nucl. Med. Biol. 40: 3-14; "Deri"), for reasons set forth in the previous Office Action.
Response to arguments
Applicant argues that a claim with "cells, liposomes, DNA aptamers, RNA aptamers, viruses, nanoparticles, and microorganisms" would be commensurate in scope with the Inventor's Declaration. Previous dependent claim 3 recited, among other things, "wherein the additional moiety is at least one of a liposome, DNA aptamer, RNA aptamer, a virus, nanoparticles, microorganisms". Applicant asserts that this language from original dependent claim 3 has been added to independent claim 1. Therefore, amended independent claim 1 is commensurate in scope with the Inventor's Declaration.
Applicant’s arguments have been fully considered but are not found to be persuasive. It is respectfully submitted that the recitation of liposomes, DNA aptamers, RNA aptamers, viruses, nanoparticles, and microorganisms as additional moieties in the amended claim is not necessarily part of an active step of the claimed invention. For example, the method is directed to preparation of a labeling agent itself, i.e. a method for preparing a labeling agent, the method comprising: (a) providing a compound including a chelating moiety and a conjugation moiety; and (b) mixing the compound with a radionuclide to create the labeling agent before reacting the compound with an additional moiety, etc. As such recitation of the identity of the additional moiety which is to be reacted is interpreted as an intended use of the claimed method of preparing a labeling agent.
Applicant further argues that the Inventor's Declaration reviewed Vosjan and provided evidence that biological entities such as cells, liposomes, DNA aptamers, RNA aptamers, viruses, nanoparticles, and microorganisms, will catastrophically suffer from the attempt to radiolabel them with 89Zr using the methodology of Vosjan (which was used by Deri). In the regard, the methodology of Vosjan first reacts the biological entity with Desferrioxamine-isothiocyanate (DFO-NCS) to attach DFO to the biological entity, then presents ⁸⁹Zr to the biological entity-DFO construct. This approach is undesirable when the biological entity is not stable under the DFO-NCS labeling conditions (pH 9.0 as disclosed in the abstract of Vosjan) or by virtue of the time required for this step (2.5 hours as disclosed in the abstract of Vosjan.). Applicant asserts that amended independent claim 1 is significantly different with respect to the method of Vosjan (which was used by Deri) in that independent claim 1 recites mixing the compound with a radionuclide to create the labeling agent before reacting the compound with an additional moiety. The approach only requires one step to radiolabel the biological entity. The method of Vosjan requires a two-step process with significant time in between. The biological entity may be deleteriously affected by the two-step process of Vosjan, given the harsh labeling conditions and long labeling time of Vosjan. Perk uses a similar process as Vosjan. Thus, Deri's use of the method of Vosjan and Perk does not teach the step of independent claim 1 which recites mixing the compound with a radionuclide to create the labeling agent before reacting the compound with an additional moiety.
Applicant’s arguments have been fully considered. With regard to arguments directed to the order of mixing the compound with a radionuclide to create the labeling agent before reacting the compound with an additional moiety, 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.).
Applicant further argues that Vasalatiy and Deri are not in the same field as Vasalatiy is directed to paramagnetic metal chelate contrast agents that can enhance image contrast in magnetic resonance imaging (MRI). The citations to Exhibit 1 above show that one skilled in the art would understand that: (i) the MRI contrast agents of Vasalatiy "shorten the T1 or T2 relaxation times, respectively, of neighboring protons, leading to measurable alterations in MR signal" (see page 904 of Exhibit 1), (ii) Vasalatiy requires "large amounts of imaging agents (i.e., many log orders higher compared with that needed for PET or SPECT)" (see page 905 of Exhibit 1), and (iii) the MRI of Vasalatiy does not use ionizing radiation (see Table 1 of Exhibit 1).
Applicant’s arguments have been fully considered. Each of Vasalatiy and Deri are directed to in vivo imaging, which is reasonable within the same field of endeavor such that one may substitute a metal for another according the known and desired method of imaging, MRI vs PET.
Applicant further argues that the prior art teaches away from the claimed invention. Applicant asserts that Vasalatiy is working in a different field endeavor (i.e., MRI) using contrast agents that "shorten the T1 or T2 relaxation times, respectively, of neighboring protons, leading to measurable alterations in MR signal" (see page 904 of Exhibit 1) and require "large amounts of imaging agents (i.e., many log orders higher compared with that needed for PET or SPECT)" (see page 905 of Exhibit 1), why would one seek out the alternative imaging agents of Deri wherein a nanomolar amount of the chosen radiolabeled agent is administered to the patient/subject, and PET takes advantage of the unique properties of radioactive isotopes that decay via positron emission? See pages 908-909 of Exhibit 1. Thus, Vasalatiy and Deri "may be said to teach away" from the invention of amended independent claim 1.
Applicant’s arguments have been fully considered but are not found to be persuasive. With regard to allegations of teaching away, see MPEP 2145. A prior art reference that “teaches away” from the claimed invention is a significant factor to be considered in determining obviousness. However, “the nature of the teaching is highly relevant and must be weighed in substance. A known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use.” In reGurley, 27 F.3d 551, 553, 31 USPQ2d 1130, 1132 (Fed. Cir. 1994) (Claims were directed to an epoxy resin based printed circuit material. A prior art reference disclosed a polyester-imide resin based printed circuit material, and taught that although epoxy resin based materials have acceptable stability and some degree of flexibility, they are inferior to polyester-imide resin based materials. The court held the claims would have been obvious over the prior art because the reference taught epoxy resin based material was useful for the inventor’s purpose, applicant did not distinguish the claimed epoxy from the prior art epoxy, and applicant asserted no discovery beyond what was known to the art.).
Furthermore, “the prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed….” In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004). See also UCB, Inc. v. Actavis Labs, UT, Inc., 65 F.4th 679, 692, 2023 USPQ2d 448 (Fed. Cir. 2023) (“a reference does not teach away if it merely expresses a general preference for an alternative invention but does not criticize, discredit or otherwise discourage investigation into the invention claimed.”) (internal quotations omitted) (quoting DePuy Spine, Inc. v. Medtronic Sofamor Danek, Inc., 567 F.3d 1314, 1327 (Fed. Cir. 2009)); and Schwendimann v. Neenah, Inc., 82 F.4th 1371, 1381, 2023 USPQ2d 1173 (Fed. Cir. 2023) (“Although Oez [the prior art] used a white pigment with a cross-linking polymer, it does not discourage a skilled artisan from using the white pigment without a cross-linking polymer or lead the skilled artisan in a direction divergent from the path taken in the Appealed Patents. Thus, Oez's disclosure is substantial evidence that supports the Board's finding that Oez does not teach away from the proposed combination.”). In the instant case it is considered that the prior art does not discredit substitution of a metal ion as such it is considered that the prior art does not rise to the level of teaching away from the claimed invention.
Claim(s) 1, 3-6, 11, 12, 14, 19 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Lee et al. (WO 15/178618).
Lee teaches a method for labeling exosomes with a radioactive substance using amine groups on surfaces of the exosomes; exosomes prepared thereby; an imaging composition comprising the same; and an imaging method. According to the method of the present application, the exosomes can be stably labeled at high labeling efficiency, and the exosomes prepared by the method of the present application can be favorably used as an agent for nuclear medicine imaging and therapeutic imaging for confirming the biological distribution of exosomes and the migration or not of exosomes to target organs and target diseases in animals including a human being (abstract).
In one aspect the present disclosure provides a method of providing a cell-derived exosome; And treating the exosome surface with N-Hydroxysuccinimide-azadibenzocyclooctyne (NHS-ADIBO); And mixing the treated exosomes with a chelator-radioactive material into which N3 is introduced to perform a reaction with the amine groups present on the surface of the exosome and the chelator. It is introduced into the exosomes, provides a radioactive material labeling method of exosomes. Exosomes herein means extracellular vesicles, and include exosomes and exosomes that can be secreted out of cells as cell-derived materials.
In one embodiment of the present invention, the chelator incorporating N3 used in the methods herein is not limited as long as it can react with NHS-ADIBO in a reaction based on click chemistry, for example… p -SCN-Bn-DFO (1- (4-Isothiocyanatophenyl) -3- [6,17-dihyroxy-7,10,18,21-tetraoxo-27- [N-acet ylhydroxylamino) -6,11,17,22-tetraazaheptaeicosane] thiourea), etc. In the method according to the present invention, the chelator is labeled with a radioisotope, which is. 89 Zr, etc.
Exosomes are nanoscale vesicles that are naturally produced in cells, and contain proteins and genetic information. They transmit various signals, including genetic information, to other cells to develop, proliferate, differentiate, regulate immune, and vascular blood vessels. It is known to be involved in the production and progress of various diseases. Exosomes can be isolated from various cells with reference to techniques known in the art or the methods described in the Examples herein and the like.
In the method herein, the free amine group (NH2) on the surface of the exosomes reacts with the chelator linked to the radioisotope. As long as it can react with free amine groups (NH2 ), any material may be used, including, but not limited to, NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid), DOTA ( 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), TETA (1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid), DFO (3- [6,17-dihyroxy-7,10,18,21-tetraoxo-27- (N-acetylhydroxylamino) -6,11,17,22-tetraazaheptaeicosane] thiourea), diethylenetriaminepentaacetic acid (DTPA), N .sub.2 S .sub.2 (diaminedithiol ), p -SCN-Bn-NOTA (2- (4'-isothiocyanatobenzyl) -1,4,7-triazacyclononane-1,4,7-triacetic acid), NODAGA (1,4,7-triazacyclononane, 1-glutaric acid-4,7-acetic acid), p -SCN-Bn-DOTA (2- (4'-isothiocyanatobenzyl) -1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), p -SCN-Bn-DTPA (2- (4-isothiocyanatobenzyl) -diethylenetriaminepentaacetic acid), p-SCN-Bn-DFO (1- (4-Isothiocyanatophenyl) -3- [6,17-dihyroxy-7,10,18, 21-tetraoxo-27- [N-acetylhydroxylamino) -6,11,17,22-tetraazaheptaeicosane] thiourea), HYNIC (hydrazino Examples of chelators and labeled radioactive materials include nicotinic acid) such as 18 F, 68 Ga, 64 Cu, 89 Zr, 124 I and gamma-emitting radionuclides 99mTc, 111 In, 123 I, Radioactive isotopes of 125 I, or the therapeutic nucleus 67 Cu, 177 Lu, 90 Y, 186 Re, 188 Re, 131 I (page 4).
In claim 3, treated exosomes with the chelator-radioactive material is performed at pH 7.0 to pH 7.4.
In the method according to the invention, the reaction of the exosomes treated with NHS-ADIBO with the chelator-radioactive material may be carried out at about pH 7.0 to pH 7.4. In particular, it may be carried out in a phosphate buffer solution of about pH 7.0 to pH 7.4. The reaction (click chemistry) of the ADIBO compound with the chelator with N3 functionalities can be carried out at neutral pH conditions, for example pH 7.0 to pH 7.4 and at room temperature, in which case it is effectively labeled without changing the physical properties of the exosomes, see example 2.
It would have been obvious to one of ordinary skill in the art at the time of the invention to provide a labeling agent by providing a compound having a chelating moiety including a hydroxamic acid group and an isothiocyanate group and mixing the compound with a radionuclide, which is a positron emitter, to create the labeling agent before reacting the compound with an additional moiety in view of Lee. One would have been motivated to do so, with a reasonable expectation of success, because Lee teaches p-SCN-Bn-DFO to be one of a few suitable chelators linked to a radioactive isotope, including 89Zr, which may then react with a free amine group on the surface of an exosome.
With regard to the limitation of claims 1, 3-6, 11, 12 and 14 wherein the additional moiety is at least one of a liposome, DNA aptamer, RNA aptamer, a virus, nanoparticles, and microorganisms, it is noted that reaction with an additional moiety is not an active step in the claimed method and does not distinguish over the methods taught in Lee, as the labeling agent is intended to be reacted with an additional moiety (i.e. see claims 19 and 20 which positively recite further reacting the labeling agent with an additional moiety). Further, it is noted that an exosome is a nanoparticle. With regard to claim 19, reaction between exosome is performed with the claimed pH range. With regard to claim 20, general conditions for exosome labeling with a radiolabeled N3 chelator and determination of labeling efficiency is taught in Example 2, as well as measuring serum stability up to one hour was performed. It would have been obvious to one of ordinary skill in the art to modify reaction conditions within the claimed time frame including reaction time as a means of optimization of reaction conditions and efficiency. Furthermore, differences in concentration or temperature will generally not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); In re Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382; or In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969).
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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/LHS/
/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618
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