DETAILED ACTION
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 15 August 2025 has been entered, and the arguments presented therein have been fully considered. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Status of Claims
Claims 1-31 are pending.
Claims 12-15 and 20-28 have been withdrawn from consideration.
Claims 1-11, 16-19, and 29-31 are subject to substantive examination.
Claim Interpretation
The examiner notes that the claimed term “antimicrobial” has been defined to include not only antibiotic (i.e. antibacterial) and antifungal agents, but also antivirals. See the instant specification, page 1, paragraph 0002. An applicant is entitled to be their own lexicographer and may rebut the presumption that claim terms are to be given their ordinary and customary meaning by clearly setting forth a definition of the term that is different from its ordinary and customary meaning(s) in the specification at the relevant time. See MPEP 2111.01(IV)(A). In this case, defining the term “antimicrobial” to include antivirals would appear to differ from the ordinary and customary meaning of the term. Nevertheless, as applicant has clearly defined the term “antimicrobial” in this way, the term “antimicrobial” is not indefinite.
Applicant does not appear to dispute this position in applicant’s response on 15 August 2025.
Claim Rejections - 35 USC § 103 – Obviousness
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.
Claim(s) 1-9, 11, 16, 18-19, and 31 is/are rejected under 35 U.S.C. 103 as being unpatentable over Guo et al. (US 2015/0246137 A1) in view of Birkmayer (US 2003/0021772 A1).
Guo et al. (hereafter referred to as Guo) is drawn to delivery of an active agent using a liposomal delivery vehicle, as of Guo, title and abstract. Although it does not appear to be the main focus of the document, Guo teaches lipid coated calcium phosphate nanoparticles, as of Guo, paragraphs 0070 and 0269. Guo teaches in paragraph 0269 that said lipid coated calcium phosphate has been developed to deliver “diverse biomolecules.”
Guo does not teach nicotinamide adenine dinucleotide.
Birkmayer is drawn to the therapeutic effects of nicotinamide adenine dinucleotide (NADH) or nicotinamide adenine dinucleotide phosphate (NADPH), as of Birkmayer, title and abstract. NADH/NADPH are useful for treating the effects of sleep deprivation, as of Birkmayer, title, abstract, and claim 1. Birkmayer teaches parenteral modes of administration in paragraph 0019.
Birkmayer does not teach the required nanoparticle.
It would have been prima facie obvious for one of ordinary skill in the art to have used the NAD/NADPH of Birkmayer as the therapeutic agent in the composition of Guo. Guo is drawn to a lipid coated calcium phosphate nanoparticle which can be used to deliver diverse biomolecules. Birkmayer teaches that NADH/NADPH are biomolecules that have therapeutic efficacy. As such, the skilled artisan would have been motivated to have used the vehicle of Guo to have predictably delivered the NADH/NADPH of Birkmayer with a reasonable expectation of success in order to have had predictable therapeutic efficacy in treating the symptoms of sleep deprivation with a reasonable expectation of success.
As to claim 1, the claim requires that the nanoparticle is sized from at least 50 nm to less than 1000 nm. Guo appears to teach particle sizes in the range of 1 nm to 1000 nm in paragraph 0104. This overlaps with the claimed range. While the prior art does not disclose the exact claimed values, but does overlap: in such instances even a slight overlap in range establishes a prima facie case of obviousness. See MPEP 2144.05(I).
As to claims 2-3, these claims require particular weight percentages of NADH. Birkmayer teaches about 3% to about 10% NADH in paragraph 0023. This is within the claimed range of both claims 2 and 3.
As to claim 4, the claim requires a specific weight percentage of lipid bilayer. While Guo provides teachings related to lipid amounts, as of e.g. Guo, paragraph 0127, Guo does not appear to specifically teach the percentage of the composition that is lipid bilayer. Nevertheless, generally, differences in concentration between the prior art and claimed invention will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical. See MPEP 2144.05(II)(A). In this case, no evidence of the criticality of the mass percentage of the lipid bilayer has been provided in the record. Additionally, where 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 MPEP 2144.05(II)(A). In this case, the general conditions of a lipid bilayer coated calcium phosphate particle have been taught by Guo. As such, it would not have been inventive to have discovered the optimum or workable ranges of amount of the lipid bilayer by routine experimentation.
As to claim 5, Guo teaches phosphatidylcholine and other lipids in paragraph 0092.
As to claim 6, Guo teaches a PEGylated lipid in at least paragraphs 0054 and 0127.
As to claim 7, Guo teaches about 5 mol% to about 20 mol% lipid-PEG conjugate in paragraph 0127.
As to claim 8, Guo teaches DOPC and DOPA in paragraph 0094.
As to claim 9, Guo teaches DSPE-PEG2000 in paragraph 0127. Because Guo did not specify the endgroup, the skilled artisan would have expected that the terminating group would have been an OH group, as this is the natural terminating group of polyethylene glycol. Regardless, elsewhere in the document, Guo teaches DSPE-mPEG, which is understood to be a methyl (i.e. C1 alkyl ether) terminating group.
As to claim 11, the claim requires a specific weight percentage of the inorganic core. While Guo provides teachings related to the presence of a calcium phosphate core, e.g. in paragraphs 0059 and 0070, Guo does not appear to specifically teach the percentage of the composition that is inorganic core of calcium phosphate. Nevertheless, generally, differences in concentration between the prior art and claimed invention will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical. See MPEP 2144.05(II)(A). In this case, no evidence of the criticality of the mass percentage of the calcium phosphate core has been provided in the record. Additionally, where 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 MPEP 2144.05(II)(A). In this case, the general conditions of a lipid bilayer coated calcium phosphate particle have been taught by Guo. As such, it would not have been inventive to have discovered the optimum or workable ranges of amount of the calcium phosphate core by routine experimentation.
As to claim 16, Guo teaches antibacterial agents in paragraph 0284.
As to claim 18, the claim requires that the nanoparticle is sized from at least 70 nm to less than 700 nm. Guo appears to teach particle sizes in the range of 1 nm to 1000 nm in paragraph 0104. This overlaps with the claimed range. While the prior art does not disclose the exact claimed values, but does overlap: in such instances even a slight overlap in range establishes a prima facie case of obviousness. See MPEP 2144.05(I).
As to claim 19, Guo teaches a pharmaceutical composition and a pharmaceutically acceptable carrier, as of paragraphs 0281-0283.
As to claim 31, Guo teaches intravenous administration at multiple locations in the reference including paragraph 0279.
Claim(s) 5 and 10 is/are rejected under 35 U.S.C. 103 as being unpatentable over Guo et al. (US 2015/0246137 A1) in view of Birkmayer (US 2003/0021772 A1), the combination further in view of Zhang et al. (US 2013/0337066 A1).
Guo is drawn to delivery of an active agent with a lipid coated calcium phosphate particle. Birkmayer teaches that the active agent to be delivered is NADH. See the rejection above over Guo in view of Birkmayer.
Neither Guo nor Birkmayer teach that the lipid bilayer comprises lipids obtained from the cell membrane extract of a red blood cell, macrophage, neutrophil, or platelet.
Zhang et al. (hereafter referred to as Zhang) is drawn to membrane encapsulated nanoparticles, as of Zhang, title, abstract, and figure 1, reproduced below.
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While Example 2 of Zhang appears to be drawn to red blood cell membrane coated polymeric nanoparticles, as of Zhang, page 22, Zhang teaches membrane coated calcium phosphate particles in paragraph 0107, in which Zhang refers to such particles as “phosphate calcium particle[s].”
Zhang does not teach NADH.
It would have been prima facie obvious for one of ordinary skill in the art to have coated the particle of Guo with the red blood cell membrane extract of Zhang. Guo is drawn to a calcium phosphate particle coated with lipids that form a lipid bilayer for the delivery of an active agent. Zhang is drawn to red blood cell membrane coated particles, including calcium phosphate particles, also for the delivery of an active agent. As such, the skilled artisan would have been motivated to have substituted the membranes of Zhang, obtained from red blood cells or other cell types, in place of the membrane of Guo, obtained from synthetic lipids, in order to have predictably coated the calcium phosphate nanoparticle of Guo for predictable delivery of active agents such as NADH (e.g. from Birkmayer) with a reasonable expectation of success. The simple substitution of one known element (e.g. red blood cell membrane lipids, as of Zhang) in place of another (e.g. synthetic lipids, e.g. as of Guo) in order to achieve predictable results (coating of an inorganic nanoparticle for drug delivery) is prima facie obvious. See MPEP 2143, Exemplary Rationale B.
Claim(s) 17 is/are rejected under 35 U.S.C. 103 as being unpatentable over Guo et al. (US 2015/0246137 A1) in view of Birkmayer (US 2003/0021772 A1), the combination further in view of Patil et al. (US 2014/0296526 A1).
Guo is drawn to delivery of an active agent with a lipid coated calcium phosphate particle. Birkmayer teaches that the active agent to be delivered is NADH. See the rejection above over Guo in view of Birkmayer. Guo teaches antibacterial agents in paragraphs 0283-0285, along with antifungal agents.
Guo does not teach genatmicin, azithromycin, and ciprofloxacin.
Patil et al. (hereafter referred to as Patil) is drawn to particular antibacterial compounds, as of Patil, title and abstract. Elsewhere in the reference, Patil teaches that gentamicin, azithromycin, and ciprofloxacin are antibacterial agents, as of paragraphs 0095, 0101, and 0106.
Patil does not teach NADH and does not teach a lipid coated calcium phosphate particle.
It would have been prima facie obvious for one of ordinary skill in the art to have used the gentamicin, azithromycin, and ciprofloxacin of Patil as the antibacterial agents in the composition of Guo in view of Birkmayer. Guo and Birkmayer teach a composition comprising a lipid coated particle which may include antibacterial agents. Guo does not specify the chemical identity of the antibacterial agents. Nevertheless, Patil teaches that amikacin, gentamicin, azithromycin, and ciprofloxacin are antibacterial agents. As such, the skilled artisan would have been motivated to have used the antibacterial agents of Patil in the composition of Guo in view of Birkmayer in order to have predictably have provided an antibacterial effect with a reasonable expectation of success, as an antibacterial effect is desired by Guo.
Claim(s) 29-30 is/are rejected under 35 U.S.C. 103 as being unpatentable over Guo et al. (US 2015/0246137 A1) in view of Birkmayer (US 2003/0021772 A1), the combination further in view of Stavchansky et al. (US 2012/0130300 A1).
Guo is drawn to delivery of an active agent with a lipid coated calcium phosphate particle. Birkmayer teaches that the active agent to be delivered is NADH. See the rejection above over Guo in view of Birkmayer. Guo teaches antivirals in paragraph 0156 and antifungals, also in paragraph 0156.
Guo does not teach acyclovir, as of claim 29, nor does Guo teach fluconazole, as of claim 30.
Stavchansky et al. (hereafter referred to as Stavchansky) is drawn to a zero-order release drug delivery system, as of Stavchansky, title and abstract. Stavchansky teaches acyclovir as an antiviral, as of paragraph 0132. Stavchansky teaches fluconazole as an antifungal, as of paragraph 0054.
Stavchansky does not teach a metal-organic framework.
It would have been prima facie obvious for one of ordinary skill in the art to have used the acyclovir of Stavchansky as the antiviral agent in the composition of Guo in view of Birkmayer. It also would have been prima facie obvious for one of ordinary skill in the art to have used the fluconazole of Stavchansky as the antifungal agent in the composition of Guo in view of Birkmayer. Guo and Birkmayer teach a composition comprising a lipid coated particle which may include antiviral and antifungal agents. Guo does not specify the chemical identity of the antiviral and antifungal agents. Nevertheless, Stavchansky teaches that acyclovir is an antiviral agent and that fluconazole is an antifungal agent. As such, the skilled artisan would have been motivated to have used the antiviral and/or antifungal agents of Stavchansky in the composition of Guo in view of Birkmayer in order to have predictably have provided an antiviral and/or antifungal effect with a reasonable expectation of success, as an antibacterial effect is desired by Guo.
As to claim 29, the acyclovir of paragraph 0132 of Stavchansky reads on the claimed requirement.
As to claim 30, the fluconazole of paragraph 0054 of Stavchansky reads on this claimed requirement.
Claim(s) 1-9, 11, 16, 18-19, and 31 is/are rejected under 35 U.S.C. 103 as being unpatentable over Guo et al. (US 2015/0246137 A1) in view of Birkmayer (US 2003/0021772 A1), the combination further in view of Miller (US 2016/0375049 A1).
Claim(s) 5 and 10 is/are rejected under 35 U.S.C. 103 as being unpatentable over Guo et al. (US 2015/0246137 A1) in view of Birkmayer (US 2003/0021772 A1) and Zhang et al. (US 2013/0337066 A1), the combination further in view of Miller (US 2016/0375049 A1).
Claim(s) 17 is/are rejected under 35 U.S.C. 103 as being unpatentable over Guo et al. (US 2015/0246137 A1) in view of Birkmayer (US 2003/0021772 A1) and Patil et al. (US 2014/0296526 A1), the combination further in view of Miller (US 2016/0375049 A1).
Claim(s) 29-30 is/are rejected under 35 U.S.C. 103 as being unpatentable over Guo et al. (US 2015/0246137 A1) in view of Birkmayer (US 2003/0021772 A1), and Stavchansky et al. (US 2012/0130300 A1), the combination further in view of Miller (US 2016/0375049 A1).
Guo is drawn to delivery of an active agent with a lipid coated calcium phosphate particle. Birkmayer teaches that the active agent to be delivered is NADH. See the rejection above over Guo in view of Birkmayer. Zhang teaches a membrane obtained from various blood cells such as erythrocytes, and Patil teaches specific antibacterial agents.
For the purposes of this rejection, the examiner takes the position that, purely en arguendo and with regard to this rejection only, none of the applied references provide motivation for the skilled artisan to have combined a calcium phosphate particle with NADH.
Miller is drawn to a dinucleotide phosphate in a nanoparticle, as of Miller, title, abstract, and the figure on the front page of the document, which is reproduced below.
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The nanoparticle of Miller may be a calcium phosphate nanoparticle, as of Miller, paragraphs 0156-0157, which are reproduced below.
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Also see Miller, paragraph 0162. As such, Miller teaches combining calcium phosphate nanoparticles with dinucleotide phosphate.
Miller does not teach NAD+ or NADH.
It would have been prima facie obvious for one of ordinary skill in the art to have used a calcium phosphate nanoparticle coated with lipids to have delivered a dinucleotide phosphate active agent, such as NADH, as of Birkmayer. Miller is drawn to the use of a nanoparticle to deliver a dinucleotide phosphate, and suggests the use of a calcium phosphate nanoparticle as of paragraphs 0156-0157. As Birkmayer teaches that NADH has therapeutic effects, the skilled artisan would have been motivated to have combined the NADH of Birkmayer with the particle of Guo because Miller teaches that calcium phosphate nanoparticles covered by a surface lipid layer can be used for predictably delivery of dinucleotide phosphates (such as NADH) with a reasonable expectation of success.
Response to Arguments
Applicant has presented arguments as of applicant’s response on 15 August 2025 (hereafter referred to as applicant’s response). These arguments are addressed below. The examiner clarifies that this response begins with applicant’s arguments on page 10, section entitled “Guo in view of Birkmayer.” In contrast, the arguments present on page 8 through the end of the first paragraph of page 10 of applicant’s response are addressed at the end of this document.
In applicant’s response on 15 August 2025 (hereafter referred to as applicant’s response), applicant takes the position that Guo is directed to low [water] solubility bioactive compounds; whereas, in contrast, the NAD(H) recited by the instant claims is highly water-soluble, as of applicant’s response, paragraph bridging pages 10-11. Applicant argues that while Guo teaches the delivery of highly water-soluble compounds under certain conditions, these conditions entail precipitating said compounds (e.g. with indium) to render them to have a low water solubility, as of applicant’s response, page 11.
This is not persuasive; the examiner takes the position that this is an overly narrow readings of the teachings of Guo. In support of this position, the examiner has reproduced Example 6 from page 36 of Guo side-by-side with Example 1 of the instant application.
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The examiner notes that the above-reproduced examples from Guo and the instant specification bear crucial similarities. First, both products are described as water-in-oil reverse microemulsions. Secondly, in both cases, the active agent is introduced in aqueous phase, indicating that the active agent is water-soluble. The first two lines of paragraph 0367 from Guo indicate that the cisplatin is introduced in a solution of potassium chloride (KCl) in water. As such, both examples appear to be drawn to similar ways of encapsulating water-soluble drugs, neither of which entails precipitation of said drugs to render them insoluble.
The examiner notes that one crucial difference between Example 6 of Guo and both the claimed invention and the above-indicated example from the specification is that Example 6 of Guo lacks the required calcium phosphate core. Nevertheless, the calcium phosphate core is taught elsewhere in Guo, at least as of paragraph 0070 of Guo.
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The abbreviation “LCP” in this case is understood to refer to a lipid coated calcium phosphate nanoparticle; see paragraph 0059 of Guo. The examiner notes that various of the active agents recited in this paragraph are functional genes and silencing RNA. Functional genes and silencing RNA are water-soluble, and there is no evidence that Guo suggests precipitating these (e.g. with indium) to render them water-insoluble. While Guo indicates problems with the formulation comprising a calcium phosphate core in paragraph 0070 such as low loading ratios, it still appears that this formulation comprising a calcium phosphate core is capable of successfully delivering therapeutic agents. As such, Guo does not teach away from using a drug delivery formulation comprising a calcium phosphate core. 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. See MPEP 2145(X)(D)(1), first paragraph in section.
As such, applicant’s arguments regarding the Guo reference are not persuasive at least because the teachings of Guo are more expansive than what is indicated from applicant’s arguments.
Regarding Birkmayer, applicant appears to argue that Birkmayer is drawn to delivering NADPH precursors that must be metabolized to NADH, rather than NADH itself, as of applicant’s response, paragraph bridging pages 11-12. This is not persuasive. Birkmayer teaches delivering both NADH and NADPH, as of the abstract. As such, the skilled artisan would have been motivated to have used the formulation of Birkmayer to have delivered NADH.
Applicant then argues that the skilled artisan would not have been motivated to have formulated soluble NADH into Guo’s nanoparticles, and/or would not have been motivated to have formed a precipitate of NADH, as of applicant’s response, page 12, top paragraph. This is not persuasive. As explained above, Guo teaches forming nanoparticles from soluble ingredients without precipitating said nanoparticles. As such, contrary to applicant’s arguments, Guo does not teach away from formulating a nanoparticle comprising a water-soluble ingredient such as NADH.
The examiner previously rejected the dependent claims over the combinations of Guo in view of Birkmayer and further in view of Zhang, Patil, and Stavchansky. Applicant appears to argue that these rejections should be withdrawn for essentially the same reason that the rejection over Guo in view of Birkmayer should be withdrawn, as of applicant’s response, pages 12-13. No additional arguments regarding the teachings of Zhang, Patil, and/or Stavchansky have been presented. These arguments are not persuasive for essentially the same reasons that applicant’s arguments regarding the combination of Guo in view of Birkmayer are not persuasive.
The examiner previously rejected the instant claims over the combination of Guo in view of Birkmayer and Miller. One argument made by applicant, which has been presented on page 14, is that Miller does not provide any working examples or evidence to show that the calcium phosphate nanoparticles actually work for the delivery of dinucleoside polyphosphate analogs, let alone for NAD+ or NADH.
This is not persuasive. As an initial matter, Miller does appear to teach calcium phosphate particles in an example, as of Miller, paragraphs 0156-0157, which were discussed on page 13 of the prior office action mailed on 18 February 2025. While this example includes RNA rather than a dinucleotide phosphate such as NAD+ or NADH, the skilled artisan would have been motivated to have combined a dinucleotide phosphate, in view of the teachings of paragraph 0162 of Miller. Regarding applicant’s arguments that there would have been no expectation that this combination would have been successful, these arguments are not persuasive. Obviousness requires a reasonable expectation of success, not absolute predictability. See MPEP 2143.02, especially 2143.02(II). The examiner notes that evidence showing that there was no reasonable expectation of success may support a conclusion of non-obviousness; however, applicant’s arguments to this effect on page 14 of applicant’s response appears to be speculation rather than evidence.
The examiner notes that applicant cites paragraph 0157 of Miller, as of applicant’s response, page 14. This paragraph has been reproduced below.
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This example appears to indicate that intracellular delivery is desirable. Furthermore, the skilled artisan would have understood that nucleic acids generally have to be delivered intracellularly to be effective; as such, the skilled artisan would have been motivated to have used a calcium phosphate particle to have delivered a payload intracellularly.
Applicant then makes the following argument on page 14, relevant text reproduced below.
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These arguments appear to present speculative reasons as to why there would have been an alleged lack of success at using the composition of Miller to have delivered the recited active agent. Such speculation is not persuasive. Obviousness requires a reasonable expectation of success, not absolute predictability. See MPEP 2143.02, especially 2143.02(II). The examiner notes that evidence showing that there was no reasonable expectation of success may support a conclusion of non-obviousness; however, the above-indicated arguments appear to be speculation rather than evidence.
Applicant then makes an argument regarding the P2X3 (also known as P2X3) receptor, citing paragraph 0119 of Miller. The examiner has reproduced paragraph 0119 of Miller below.
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As best understood by the examiner, the application referred to a PCT/GB2013/051377 was published as Miller et al. (US 2015/0119352 A1). This reference (hereafter referred to as Lozovaya after the second named inventor) is drawn to a dinucleoside polyphosphate analog for treatment of pain, as of Lozovaya, title and abstract.
One argument made by applicant on the last paragraph of page 14 of applicant’s response appears to relate to intracellular release vs. extracellular release. As best understood by the examiner, applicant’s argument appears to be that Miller is drawn to extracellular release because the composition of Miller targets the P2X3 receptor which is present on the outside of a cell; however, the invention of the instant application is for intracellular release.
In view of this argument, the examiner conducted an additional search related to P2X3. One reference found during the course of this search is Demnitz et al. (US 2008/0021034 A1), which teaches the following, as of paragraph 0007, relevant text reproduced below.
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The above-reproduced text indicates that P2X3 is present both intracellularly and extracellularly. As such, to the extent that applicant is arguing that an active agent which operates by interacting with P2X3 would not have been successful had it been released intracellularly, this argument is not persuasive because P2X3 is present intracellularly.
The examiner clarifies that the Lozovaya and Demnitz references are not part of the statement of rejection, and are newly cited by the examiner in order to best respond to applicant’s arguments.
The examiner previously rejected the dependent claims over the combinations of Guo in view of Birkmayer and Miller and further in view of Zhang, Patil, and Stavchansky. Applicant appears to argue that these rejections should be withdrawn for essentially the same reason that the rejection over Guo in view of Birkmayer should be withdrawn, as of applicant’s response, pages 15-16. No additional arguments regarding the teachings of Zhang, Patil, and/or Stavchansky have been presented. These arguments are not persuasive for essentially the same reasons that applicant’s arguments regarding the combination of Guo in view of Birkmayer and Miller are not persuasive.
Applicant has provided additional arguments that further explain the invention but do not appear to be directed to the teaching of a particular reference, as of applicant’s response, page 8-9 as well as the top of page 10. One argument made by applicant in this section is the following.
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This is not persuasive. The name “NAD+” has a “+” superscript; the examiner understands this to represent a positive charge. NADH would appear to imply a neutral charge due to the lack of a charge symbol in the name. As such, applicant’s argument that NAD+ is negatively charged does not appear to be persuasive.
Applicant’s arguments further emphasize the importance of delivering NAD(H) intracellularly, as of applicant’s response, page 9, as well as alleged lack of reasonable expectation of successfully achieving such delivery. In response, the examiner takes the position that there would have been a reasonable expectation of successfully delivering a hydrophilic therapeutic agent intracellularly as of the effective filing date. Such delivery is described by Guo. Such intracellular delivery (of a hydrophilic therapeutic agent that differs from NAD(H)) also occurred in the commercially available mRNA COVID-19 vaccines which had been administered to millions of people prior to the earliest effective filing date of 23 July 2021. See e.g. Schoenmaker et al. (International Journal of Pharmaceutics, Vol. 601, 2021, Article 120586, pages 1-13), which provides a review of the mRNA COVID-19 vaccines. Schoenmaker discusses intracellular delivery as of page 2, right column, section 2.1, specifically first paragraph in section. The examiner clarifies that Schoenmaker is not part of the statement of rejection, and was cited to rebut applicant’s argument that intracellular delivery would have lacked a reasonable expectation of success prior to the effective filing date of the instant application.
Applicant then argues that the nanoparticles of the instant invention show clear therapeutic benefit in treating sepsis, as of applicant’s response, paragraph bridging pages 9-10. Applicant cites figures 5-7 in applicant’s response. As representative, the examiner has reproduced figure 6B below.
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The above-reproduced figure does appear to show statistically significant differences between various entries on the bar graph. For example, the Control, the entry labeled “LPS+NAD+-LP-CaP” and “LPS+NAD+-LP-MOF” appear to show small amounts of IL-6 (e.g. at maximum about 100-150 of the units measured on the y-axis). In contrast, various other examples show more than an order of magnitude increase in IL-6. Nevertheless, the relationship between this graph and treatment of sepsis is unclear to the examiner and does not appear to have been explained by applicant. Applicant has the burden of explaining data that applicant proffers as evidence of non-obviousness. See MPEP 716.02(b)(II). Applicant has not met this burden by merely mentioning figures 5-7 with no additional explanation.
Note Regarding Cationic Lipids
During the course of addressing applicant’s arguments, the examiner noted the following issue regarding cationic lipids. This issue was not addressed by applicant’s arguments. Nevertheless, the examiner has chosen to address this issue as it is the examiner’s opinion that it may be relevant for patentability determination.
In applicant’s response, applicant appears to argue that the claimed invention achieves intracellular delivery, as of applicant’s response, page 9. As best understood by the examiner, as of the effective filing date, the majority of drug delivery vehicles intended for intracellular delivery comprise cationic or ionizable cationic species. This phenomenon was observed in the mRNA COVID-19 vaccines which deliver mRNA intracellularly. See Schoenmaker, page 8, figure 6, which indicates the presence of ionizable cationic lipids. Also see Guo, paragraph 0070, which teaches the well-known cationic lipid which goes by the abbreviation “DOTAP.” Guo teaches that the cationic lipid DOTAP allows the nanoparticles to be internalized by tumor cells more efficiently and to subsequently escape from the lysosomes in paragraph 0070.
However, in the instant invention, applicant did not appear to use cationic excipients. In contrast, the instant specification on page 42, paragraph 0131 discloses DOPA; this abbreviation refers to dioleoyl phosphatidic acid which is an anionic lipid.
As such, it appears that applicant may have achieved intracellular delivery in the absence of a cationic lipid. The examiner suggested that applicant review this issue as it may represent a significant difference between the claimed invention and the prior art.
The examiner clarifies that
The inclusion of this section of the office action should not be construed as the examiner taking the position that a particular subject matter is allowable or that a particular claim amendment would result in allowable subject matter; and
The inclusion of this section of the office action should not be construed as the examiner taking the position that an amendment to exclude cationic lipids is adequately supported by 35 U.S.C. 112(a). See MPEP 2173.05(i) for more information about the interpretation of negative limitations under 35 U.S.C. 112(a) and 112(b).
Also, applicant is not required to address the issues discussed in this section of the office action in applicant’s response to this office action.
Conclusion
No claim is allowed
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ISAAC . SHOMER
Primary Examiner
Art Unit 1612
/ISAAC SHOMER/ Primary Examiner, Art Unit 1612