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, drawn to nanoparticles comprising an antiretroviral drug and a pharmaceutical composition comprising a nanoparticle in the reply filed on 07/09/2026 is acknowledged.
Applicant’s further election without traverse of AZT-TP as the species of antiretroviral drug and Fe3+ as the species of metal cation in the reply filed on 07/09/2026 is acknowledged.
Claims 9-10 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 07/09/2026.
Claims 11-13 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 07/09/2026.
Claims 1-8 and 14 are under current examination. The claims were read in view of the species elections detailed above.
Priority
This application is a DIV of Application 17/294,149, filed 05/14/2021 which is a national stage entry of PCT/EP2019/081301, filed 11/14/2019. Foreign priority has been claimed to EP 18306506.9, filed 11/16/2018. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55 in Application 17/294,149.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 08/09/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the Examiner.
Drawings
The drawings are objected to because the graphs of Figure 9 are blurry and the axis labels cannot be read. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
Claim 2 is objected to because of the following informalities: it is suggested that the abbreviation “AZT-TP” should be defined.
Claim 6 is objected to because of the following informalities: it is suggested that “0,03” and “0,3” should be formatted as “0.03” and “0.3”, respectively.
Claim 7 is objected to because of the following informalities: for consistency in the claims, it is suggested that “Fe” and “chitosan/Fe complex” should read “Fe3+” and “chitosan/Fe3+ complex”, respectively.
Claim 14 is objected to because of the following informalities: it is suggested that “Fe3+” in line 2 should be formatted as “Fe3+”; further, for consistency in the claim, it is suggested that “Fe” and “chitosan/Fe complex” should read “Fe3+” and “chitosan/Fe3+ complex”, respectively. It is further suggested that the abbreviation “AZT-TP” should be defined.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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.
Claims 6-7 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claim 6 recites the limitation "the maximum ratio of the amount of the antiretroviral drug in the nanoparticle relative to the amount of the chitosan in the nanoparticle is comprised between 0,03 and 0,3”. No units are associated with the recited ratio amounts (mol, weight, etc.) which renders the metes and bounds of the claim uncertain. Further, the term “maximum ratio” implies the presence of multiple ratios of the amount of the antiretroviral drug in the nanoparticle relative to the amount of the chitosan in the particle, and it is unclear how a single nanoparticle can have a “maximum” ratio. For purposes of examination and applying prior art, the Examiner interprets that claim 6 requires a weight ratio of antiretroviral drug to chitosan between 0.03 and 0.3.
Claim 7 recites the limitation "the chitosan/Fe complex" in line 2. There is insufficient antecedent basis for this limitation in the claim as no chitosan/Fe complex is previously recited. Claim 1, from which claim 7 depends recites “an encapsulation complex, said complex comprising chitosan and a metal cation”. It is suggested that Application can recite “with respect to the weight of the encapsulation complex” in claim 7.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-4 and 8 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Gref et al. (US 2015/0150981 A1, published June 4th, 2015; included on IDS submitted 08/09/2024), hereafter “Gref”.
Regarding instant claims 1-3, Gref discloses chitosan-modified MIL-100 nanoparticles that encapsulate AZT-TP (paragraphs [0526]-[0527]). MIL-100 denotes the iron carboxylate MOF of formula Fe₃O[C₆H₃(CO₂)₃]₂.X.nH₂O (X= F, Cl, OH) (paragraph [0383]), synthesized from FeCl3 (paragraph [0394]), and thus the MIL-100 disclosed by Gref comprises Fe3+ metal cations (see also paragraph [0206] which discloses that MIL-100 is an iron(III) carboxylate solid).
Regarding instant claim 4, Gref discloses that chitosan-modified MIL-100 nanoparticles have an average diameter of 213 ± 3 nm (paragraphs [0517]-[0518], including Table 3).
Regarding instant claim 8, Gref discloses that MOF solids can be used as a medicament (claim 20) when loaded with a pharmaceutically active ingredient (paragraph [0281]); the chitosan-modified MIL-100 nanoparticles encapsulating AZT-TP disclosed by Gref are therefore interpreted to meet the limitation of a pharmaceutical composition.
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 1-8 and 14 are rejected under 35 U.S.C. 103 as being unpatentable over Giacalone et al. (“Drug-Induced Nanocarrier Assembly as a Strategy for the Cellular Delivery of Nucleotides and Nucleotide Analogues” Biomacromolecules 2013, 14, 737-742; included on IDS submitted 08/09/2024), hereafter ”Giacalone I” in view of Giacalone et al. (“Stabilization and cellular delivery of chitosan-polyphosphate nanoparticles by incorporation of iron” Journal of Controlled Release 2014, 194, 211-219; included on IDS submitted 08/09/2024).
Regarding instant claims 1-2, Giacalone I teaches that the drug AZT-TP can induce ionotropic gelation of chitosan, leading to CS/AZT-TP nanoparticles with high drug entrapment efficiency and loading rate (see entire document, particularly abstract). AZT-TP displays important pharmacological activities for the treatment of HIV (abstract) and can display antiviral activity (pg. 737, “Introduction”, paragraph 1). As the nanoparticles of Giacalone I are formed from gelation of chitosan and entrap AZT-TP, it is interpreted that the AZT-TP is encapsulated in an encapsulation complex comprising chitosan.
Regarding instant claim 4, Giacalone I teaches that the AZT-TP-containing nanoparticles have a mean size of 204 ± 4 nm at critical N/P ratios (see Table 1 at pg. 740), and a mean size less than 300 nm at other various N/P ratios (see Figure 2 at pg. 739).
Regarding instant claim 5, Giacalone I teaches that the nanoparticles have high drug entrapment efficiency and loading rate up to 44% by weight (abstract and Table 2 at pg. 740), overlapping the claimed range. Per MPEP 2144.05 I., “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990)”.
Regarding instant claim 6, Giacalone I teaches the addition of 0.02 mL of a 13.8 mg/mL AZT-TP stock solution (0.276 g AZT-TP) to 1 mL of a 1 mg/mL CS solution (1 mg chitosan) (pg. 737-738, “2.2 Preparation of Nanoparticles”), resulting in a weight ratio of drug to chitosan of 0.276, consistent with the range instantly claimed. Giacalone I further teaches that the amounts of components can be varied to give various N/P ratios, with an increase in triphosphate molecule concentration resulting in a decreasing N/P ratio (pg. 737-738, “2.2 Preparation of Nanoparticles” and pg. 739-740, “3.2 Characterization of CS/ATP and CS/AZT-TP Nanoparticles”). The size and ζ potential of the particles is taught to be dependent on the N/P ratio (pg. 739-740, “3.2 Characterization of CS/ATP and CS/AZT-TP Nanoparticles” and Figure 2), suggesting to one of ordinary skill in the art the routine optimization of drug to chitosan ratio to achieve a desired size and ζ potential. Per MPEP 2144.05 II. A., “"[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." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)”.
Regarding instant claim 8, as noted above, Giacalone I teaches that AZT-TP displays important pharmacological activities for the treatment of HIV (abstract) and can display antiviral activity (pg. 737, “Introduction”, paragraph 1). Giacalone I teaches exposure of diluted nanoparticles to J774 mouse macrophages as an important target cell population of anti-HIV nucleoside analogues; because they represent a major reservoir of the HIV infection, addressing HIV infection in macrophages is crucial to achieve successful long-term treatments of HIV-infected patients (pg. 738-739, “2.6. Cell Culture and Viability Assessment” and “2.7. Evaluation of Nanoparticle Association to Cells”; pg. 740, “3.4 ATP and AZT-TP Cellular Delivery by Nanoparticles”). All formulations exhibit mild cytotoxicity, and cellular uptake of AZT-TP was found to be 2-fold higher when delivered as nanoparticles compared to the free molecules (pg. 740, “3.4 ATP and AZT-TP Cellular Delivery by Nanoparticles”). As the nanoparticle formulations of Giacalone I are capable of delivering the antiviral drug AZT-TP to a macrophage reservoir of HIV infection, they are interpreted as meeting the limitation of a pharmaceutical composition.
Regarding instant independent claim 14, as noted above, Giacalone I teaches that the drug AZT-TP can induce ionotropic gelation of chitosan, leading to CS/AZT-TP nanoparticles with high drug entrapment efficiency and loading rate (see entire document, particularly abstract). AZT-TP displays important pharmacological activities for the treatment of HIV (abstract) and can display antiviral activity (pg. 737, “Introduction”, paragraph 1). As the nanoparticles of Giacalone I are formed from gelation of chitosan and entrap AZT-TP, it is interpreted that the AZT-TP is encapsulated in an encapsulation complex comprising chitosan. Giacalone I teaches that the AZT-TP-containing nanoparticles have a mean size of 204 ± 4 nm at critical N/P ratios (see Table 1 at pg. 740), and a mean size less than 300 nm at other various N/P ratios (see Figure 2 at pg. 739). Giacalone I teaches that the nanoparticles have high drug entrapment efficiency and loading rate up to 44% by weight (abstract and Table 2 at pg. 740).
Giacalone I does not teach that the encapsulation complex comprises a metal cation (instant claim 1) of Fe3+ (instant claims 3 and 14), wherein the nanoparticle comprises from 1 to 20% of Fe in weight with respect to the chitosan/Fe complex (instant claims 7 and 14).
Giacalone II teaches that chitosan nanoparticles can be obtained by complexation with triphosphate group-containing drugs such as ATP and AZT-TP, and that there is high interest in chitosan nanoparticles for drug delivery due to the biodegradability of chitosan and the ease of the preparation process (see entire document, particularly abstract and pg. 211, “Introduction”, paragraph 1). Giacalone II further teaches that chitosan-based nanoparticles tend to readily disintegrate when diluted in physiological media (abstract), and the investigation that modification of chitosan by complexing with ferric ions prior to nanoparticle formation could provide stability improvement (pg. 211-212, “Introduction”). Complexation of chitosan was achieved with iron (III) nitrate nonahydrate, a Fe3+ metal cation (pg. 212, “2.1. Materials”), and Giacalone II teaches an iron content of 3 to 12% w/w (abstract, pg. 212, “2.2. Preparation of CS-Fe complexes”, and Table 1 at pg. 215). Nanoparticle stability in physiological conditions was found to clearly increase when using CS-Fe complexes with triphosphate group-containing drugs (pg. 215-216, “3.4 Nanoparticle behavior in physiological media”). While Giacalone II exemplifies CS-Fe complexes with TPP and ATP (abstract, Table 1 at pg. 215), they suggest that formation of such nanoparticles is also possible with AZT-TP (pg. 215, “3.2. Formation of nanoparticles from CS-Fe and triphosphate derivatives”, paragraph 1).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to modify the chitosan nanogel particles of Giacalone I with the 3 to 12% w/w Fe3+ suggested by Giacalone II, overlapping the claimed range. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success in order to improve the stability of the chitosan nanogel particles in physiological conditions, as suggested by Giacalone II. There is a reasonable expectation of success as Giacalone II exemplifies increased stability of Fe3+-containing chitosan nanogels with the triphosphate-group containing drug of ATP, and suggests that the triphosphate-containing drug AZT-TP could similarly be used. Modification of the AZT-TP-containing chitosan nanogel nanoparticles of Giacalone I with 3-12% w/w Fe3+ iron content would predictably result in nanoparticles with increased stability in physiological conditions.
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 1-5 and 8 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 4, 8-10, 14-15, 17, and 19 of U.S. Patent No. 10,738,068 B2. Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of U.S. Patent No. 10,738,068 B2 recite a nanoparticle and medicament that method that encompass the limitations of the instant claims.
The claims of U.S. Patent No. 10,738,068 B2 recite a porous crystalline MOF nanoparticle comprising the metallic ion Fe3+ comprising on its surface at least one organic surface agent selected from the group including chitosan. The nanoparticle further comprises in its pores (encapsulates) at least one pharmaceutically active principle selected from those including azidothymidine phosphate (AZTP) (AZTP is also referred to as azidothymidine triphosphate in Example 15 beginning at column 77). The claims of U.S. Patent No. 10,738,068 B2 recite a medicament (pharmaceutical composition) comprising the nanoparticle and in its pores at least one pharmaceutically active principle. The nanoparticle has a loading capacity of the pharmaceutically active principle of from 1% to 200% by weight and a particle diameter of less than 1000 nm or less than 250 nm, overlapping the claimed ranges. Per MPEP 2144.05 I., “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990)”.
Claims 1-5 and 8 are directed to an invention not patentably distinct from claims 4, 8-10, 14-15, 17, and 19 of commonly assigned U.S. Patent No. 10,738,068 B2.
The U.S. Patent and Trademark Office may not institute a derivation proceeding in the absence of a timely filed petition. The USPTO normally will not institute a derivation proceeding between applications or a patent and an application having common ownership (see 37 CFR 42.411). Commonly assigned U.S. Patent No. 10,738,068 B2, discussed above, may form the basis for a rejection of the noted claims under 35 U.S.C. 102 or 103 if the commonly assigned case qualifies as prior art under 35 U.S.C. 102(a)(2) and the patentably indistinct inventions were not commonly owned or deemed to be
commonly owned not later than the effective filing date under 35 U.S.C. 100(i) of the claimed invention.
In order for the examiner to resolve this issue the applicant or patent owner can provide a
statement under 35 U.S.C. 102(b)(2)(C) and 37 CFR 1.104(c)(4)(i) to the effect that the subject matter
and the claimed invention, not later than the effective filing date of the claimed invention, were owned
by the same person or subject to an obligation of assignment to the same person. Alternatively, the
applicant or patent owner can provide a statement under 35 U.S.C. 102(c) and 37 CFR 1.104(c)(4)(ii) to
the effect that the subject matter was developed and the claimed invention was made by or on behalf of
one or more parties to a joint research agreement that was in effect on or before the effective filing
date of the claimed invention, and the claimed invention was made as a result of activities undertaken
within the scope of the joint research agreement; the application must also be amended to disclose the
names of the parties to the joint research agreement.
A showing that the inventions were commonly owned or deemed to be commonly owned not
later than the effective filing date under 35 U.S.C. 100(i) of the claimed invention will preclude a rejection under 35 U.S.C. 102 or 103 based upon the commonly assigned case. Alternatively, applicant
may take action to amend or cancel claims such that the applications, or the patent and the application,
no longer contain claims directed to patentably indistinct inventions.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JUDITH M KAMM whose telephone number is (703)756-4575. The examiner can normally be reached M-F 8:00 am-4:30 pm EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Bethany Barham can be reached at (571)272-6175. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/BETHANY P BARHAM/Supervisory Patent Examiner, Art Unit 1611
/J.M.K./Examiner, Art Unit 1611
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