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 .
Summary
Claims 1, 3-17, 62-64, 66, 74-75, 83, 85 and 120 are pending in this office action. Claims 2, 18-37, 65, 67-73, 76-82, 84, and 98-119 are cancelled. Claims 38-39, 42, 47-55, 58, 86, 92-93, and 97 are withdrawn from consideration. Applicant is encouraged to amend the withdrawn claims such that they remain in scope with the pending claims to expedite prosecution upon allowance. All pending claims are under examination in this application.
Priority
The current application was filed on February 3, 2023 is a 371 of PCT/US2021/045038 filed August 6, 2021. The current application claims domestic priority to provisional patent application 63/062,367 filed on August 6, 2020.
Information Disclosure Statement
Receipt of the Information Disclosure Statement filed on February 17, 2026 is acknowledged. A signed copy of the document is attached to this office action.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, 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 non-obviousness.
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, 3-17, 62-64, 66, 74-75, 83, 85 and 120 are rejected under 35 U.S.C. 103 as being unpatentable over Hahn et al. (US2015/0297749A1) in view of Cui et al. (WO2019/094405A1, published in May 2019), Robinson et al. (Molecular Therapy, 2018), and Hassett et al. (Molecular Therapy, published in April 2019).
[The Examiner is going to introduce each reference and then combine them where appropriate to reject the instant claims.]
1. Hahn et al.
Hahn et al. is considered the closest prior art as it teaches low-density lipoprotein analogue nanoparticles, and composition comprising same for targeted diagnosis and treatment of liver (see title). Furthermore, Hahn et al. disclose a low-density lipoprotein-like cationic solid lipid nanoparticle targeting liver cells including parenchyma cells and non-parenchyma cells, a composition for liver target delivery, a composition for diagnosis and/or treatment of liver disease comprising the same, and a method for liver targeting of an active ingredient (see abstract).
2. Cui et al.
Cui et al. teach lipid-based nanoparticles for encapsulation and sustained release of therapeutic agents (see title). In addition, Cui et al. disclose nanoparticles comprising a lipid core comprising a sterol; and a complex comprising a cationic agent and a therapeutic agent, wherein the complex is encapsulated within the lipid core. Methods to produce the nanoparticle comprise: combining a cationic agent, a therapeutic agent, and a first water-immiscible solvent with a first aqueous solution, thereby forming a mixture comprising a complex comprising the cationic agent and the therapeutic agent; combining the mixture with a second water immiscible solvent, thereby forming an aqueous phase and an organic phase, and separating the organic phase comprising the complex; combining the organic phase comprising the complex with a sterol and a first water-miscible organic solvent; and dispersing the complex in a second aqueous solution to form a herein disclosed nanoparticle. Methods for treating a disease and for reducing nanoparticle burst rate are also disclosed (see abstract).
3. Robinson et al.
Robinson et al. teach lipid nanoparticle-delivered chemically modified mRNA which restores chloride secretion in cystic fibrosis (see title). In addition, Robinson et al. disclose that the promise of gene therapy for the treatment of cystic fibrosis has yet to be fully clinically realized despite years of effort toward correcting the underlying genetic defect in the cystic fibrosis transmembrane conductance regulator (CFTR) mRNA therapy via nanoparticle delivery represents a powerful technology for the transfer of genetic material to cells with large, widespread populations, such as airway epithelia. We deployed a clinically relevant lipid-based nanoparticle (LNP) for packaging and delivery of large chemically modified CFTR mRNA (cmCFTR) to patient-derived bronchial epithelial cells, resulting in an increase in membrane-localized CFTR and
rescue of its primary function as a chloride channel. Furthermore, nasal application of LNP-cmCFTR restored CFTR-mediated chloride secretion to conductive airway epithelia in CFTR knockout mice for at least 14 days. On day 3 post-transfection, CFTR activity peaked, recovering up to 55% of the net chloride efflux characteristic of healthy mice. This magnitude of response is superior to liposomal CFTR DNA delivery and is
comparable with outcomes observed in the currently approved drug ivacaftor. LNP-cmRNA-based systems represent a powerful platform technology for correction of cystic fibrosis and other monogenic disorders (see abstract).
4. Hassett et al.
Hassett et al. teach optimization of lipid nanoparticles for intramuscular administration of mRNA vaccines (see title). In addition, Hassett et al. disclose that mRNA vaccines have the potential to tackle many unmet medical needs that are unable to be addressed with conventional vaccine technologies. A potent and well-tolerated delivery technology is integral to fully realizing the potential of mRNA vaccines. Pre-clinical and clinical studies have demonstrated that mRNA delivered intramuscularly (IM) with first-generation lipid nanoparticles (LNPs) generates robust immune responses. Despite progress made over the past several years, there remains significant opportunity for improvement, as the most advanced LNPs were designed for intravenous (IV) delivery of siRNA to the liver. Here, we screened a panel of proprietary
biodegradable ionizable lipids for both expression and immunogenicity in a rodent model when administered IM. A subset of compounds was selected and further evaluated for tolerability, immunogenicity, and expression in rodents and non-human primates (NHPs). A lead formulation was identified that yielded a robust immune response with improved tolerability. More importantly for vaccines, increased innate immune stimulation driven by LNPs does not equate to increased immunogenicity, illustrating that mRNA vaccine tolerability can be improved without affecting potency (see abstract).
Combination of Hahn et al., Cui et al., and Robinson et al.
Regarding instant claim 1, Hahn et al., Cui et al., and Robinson et al. teach a multi-component nanoparticle. The necessary citations of Hahn et al., Cui et al., and Robinson et al. that pertain to instant claim 1 are presented in Table I. The Examiner is going to present two possible combinations of these references.
Table I
Instant Claim 1
Hahn et al., Cui et al., and Robinson et al. Citations
A nanoparticle comprising: (a) a lipid nanoparticle core comprising: (i) an ionizable lipid, (ii) a phospholipid,(iii) a structural lipid, and (iv) a PEG-lipid, and (b) a polynucleotide payload encapsulated within the core for delivery into a cell, and
I.
Hahn et al. disclose a nanoparticle comprising a lipid core (triolein, cholesteryl oleate) and a shell. The shell contains cholesterol, cationic 3-beta [N-(N',N'-dimethylaminoethane)carbamoyl]-pcholesterol (DC-chol), dioleoylphosphatidyl-ethanol amine (DOPE), and distearoylphos- phatidylethanolamine-PEG (DSPEPEG) (see Fig. 1 within Hahn et al.). The active agent is a nucleic acid (see claims 1-16 within Hahn et al.). Additionally, Hahn et al. disclose that the drug (anionic or hydrophobic active agent) may be encapsulated in the core of the LDL-like nanoparticle (see paragraph [0064] within Hahn et al.). Figure 1 illustrates this lipid nanoparticle (LNP) distribution:
Figure I
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[As stated below in (c) the designation of a core and shell (shown above) becomes arbitrary because of the claim limitation where 90% of the cationic agent (equivalent to an ionizable lipid; see paragraph [0242] within the PGPUB of the specification, US2023/0285310A1) is on the surface of the nanoparticle. If the cationic agent is disposed primarily on the outer surface of the core, then the instant claim 1 “ambiguity” is met by the Hahn et al. disclosure.]
II.
Cui et al. disclose the lipid core comprising a sterol (structural lipid) can further comprise an anionic lipid (phospholipid) or a neutral lipid (phospholipid) (see page 18, lines 10-11 within Cui et al.). In addition, Cui et al. disclose the lipid core encapsulates the complex comprising the cationic agent and the therapeutic agent (siRNA; see page 22, lines 11-12). Optionally, the nanoparticle can further contain a polymeric molecule attached to the outer surface of the lipid core, such as a PEG-lipid (see page 20, lines 19-26 within Cui et al.).
An additional combination of the core disclosed by Cui et al. and the shell containing the cationic agent as disclosed by Hahn et al. would also support an obviousness rejection.
(c) a cationic agent disposed primarily on the outer surface of the core, wherein greater than 90% of the cationic agent is on the surface of the nanoparticle; wherein the nanoparticle has a zeta potential of about 5 mV to about 15 mV at physiologic pH.
Hahn et al. disclose a cationic agent (DC-Chol) that is located on the surface of the nanoparticle.
Also, Hahn et al. disclose a nanoparticle with a zeta potential of 64.3 Mv for the cationic solid lipid nanoparticle (CSLN), or 32.1 mV for the CSLN complex with siRNA (see Table 3 within Hahn et al.). These values do not meet the claim limitation.
However, Cui et al. disclose a lipid nanoparticle having zeta potential values in the range of 5 to 15 mV (see page 22, lines 30-34 within Cui et al.). Cui et al. disclose that the cationic lipid is not on the surface of the nanoparticle (see page 23, lines 1-7 within Cui et al.). Furthermore, it is known that several factors play an important role in determining zeta potential including electrostatic charge and steric stabilization via PEG (see PTO-892 NPL V).
By modifying the cationic lipid (molar ratio / structure) and PEG-lipid a skilled artisan (POSITA; person of ordinary skill in the art) would obtain the desired zeta potential value under routine experimental conditions.
Therefore, a skilled artisan (POSITA) would combine the disclosures of Hahn et al., Cui et al., and Robinson et al. in order to teach every element of instant claim 1.
Motivation: to incorporate the nucleic acid therapeutic agent and exterior cationic lipid of Hahn et al. with the zeta potential values of Cui et al.
The remaining instant claims within this 35 U.S.C. § 103 section are directly or indirectly dependent on instant claim 1 and are taught in full by the combination of Hahn et al., Cui et al., and Robinson et al.
Regarding instant claims 3-4 and 15-17, Hahn et al., Cui et al., and Robinson et al. teach a nanoparticle comprising: (a) a lipid nanoparticle core, (b) a polynucleotide payload encapsulated within the core for delivery into a cell, and (c) a cationic agent disposed primarily on the surface,
wherein the nanoparticle exhibits a cellular accumulation of at least about 20% in epithelial cells and exhibits about 5% or greater expression in epithelial cells,
wherein the nanoparticle exhibits protein expression of about 0.5% to 50% in cells, wherein the cells are in vivo,
Please see the discussion and citations within instant claim 1 for the necessary rejection text regarding the nanoparticle composition.
Additionally, Robinson et al. disclose that a lipid nanoparticle-delivered chemically modified mRNA restores chloride secretion in cystic fibrosis (see title and abstract within Robinson et al.). Specifically, Robinson et al. disclose that the team deployed a clinically relevant lipid-based nanoparticle (LNP) for packaging and delivery of large chemically modified CFTR mRNA (cmCFTR) to patient-derived bronchial epithelial cells, resulting in an increase in membrane-localized CFTR and rescue of its primary function as a chloride channel. Furthermore, nasal application of LNP-cmCFTR restored CFTR-mediated chloride secretion to conductive airway epithelia in CFTR knockout mice for at least 14 days. On day 3 post-transfection, CFTR activity peaked, recovering up to 55% of the net chloride efflux characteristic of healthy mice (see abstract; Fig. 1D; Fig. 2C; all within Robinson et al.
Despite the fact that Robinson et al. does not disclose wherein the nanoparticle exhibits the biological instant claim limitations, it is clear from their results that all of the limitations are met by the disclosure.
Regarding instant claim 5, Hahn et al., Cui et al., and Robinson et al. teach wherein a weight ratio of the cationic agent to polynucleotide payload is about 1:1 to about 4:1, about 1.25:1 to about 3.75:1, about 1.25:1, about 2.5:1, or about 3.75:1. Hahn et al. disclose:
The weight ratio of the LDL-like nanoparticles to the weight of nucleic acids (based on the weight of 21 mer siRNA) (LDL-like nanoparticle weight/nucleic acid weight) in the nucleic acid-LDL-like nanoparticle complex of the present invention may be 10 to 50…(see paragraph [0066] within Hahn et al.).
According to specific embodiments, the LDL-like nanoparticle comprises 30 to 60 wt% of cholesteryl ester, 0.1 to 10 wt% of triclyceride, 5 to 20 wt% of cholesterol, 5 to 30 wt % of fusogenic lipid (phospholipid), 10 to 50 wt % of cationic lipid and 0.01 to 1 wt % of lipid-PEG conjugate, based on the total weight of nanoparticle…(see paragraph [0053] within Hahn et al.).
Therefore, for 10 mg lipid…10 mg lipid / 1 mg RNA; and 1 mg-5 mg cationic lipid / 1 mg RNA = 1:1 to 5:1; for 50 mg lipids; and 5 mg-25 mg cationic lipid / 1 mg RNA = 5:1 to 25:1; the total ratio of cationic lipid:nucleic acid is 1:1 to 25:1 (which signifies an overlapping region).
Regarding instant claim 6, Hahn et al., Cui et al., and Robinson et al. teach wherein the nanoparticle has a zeta potential of about 5 mV to about 10 mV. Please see the discussion and citations within instant claim 1 for the necessary rejection text regarding zeta potential.
Regarding instant claim 7, Hahn et al., Cui et al., and Robinson et al. teach wherein the lipid nanoparticle core has a neutral charge at a neutral pH. Cui et al. disclose the nanoparticle has an overall neutral charge (see page 23, lines 16-18 within Cui et al.).
Regarding instant claim 8, Hahn et al., Cui et al., and Robinson et al. teach wherein greater than 95% of the cationic agent is on the surface on the nanoparticle. Please see the discussion and citations within instant claim 1 for the necessary rejection text regarding the cationic lipid.
Regarding instant claim 9, Hahn et al., Cui et al., and Robinson et al. teach wherein at least about 50%, at least about 75%, at least about 90%, or at least about 95% of the polynucleotide or polypeptide payload is encapsulated within the core. Please see the discussion and citations within instant claim 1 for the necessary rejection text regarding the encapsulated nucleic acid. Hahn et al. disclose that the drug [anionic (nucleic acid) or hydrophobic] may be encapsulated in the core of the LDL-like nanoparticle (see paragraph [0064] within Hahn et al.).
Regarding instant claim 10, Hahn et al., Cui et al., and Robinson et al. teach wherein the nanoparticle has a polydispersity value of less than about 0.4, less than about 0.3, or less than about 0.2. Robinson et al. disclose a polydispersity value (PDI) of 0.08 (see Fig. 1B within Robinson et al.).
Regarding instant claim 11, Hahn et al., Cui et al., and Robinson et al. teach wherein the nanoparticle has a mean diameter of about 40 nm to about 150 nm, about 50 nm to about 100 nm, about 60 nm to about 120 nm, about 60 nm to about 100 nm, or about 60 nm to about 80 nm. Hahn et al. disclose that the LDL-like nanoparticle of the present invention may have an average particle diameter of 70 nm to 110 nm so
as to be easily introduced in liver cells (see paragraph [0057] within Hahn et al.).
Regarding instant claims 12-14, Hahn et al., Cui et al., and Robinson et al. teach the nanoparticle of instant claim 1, wherein a general polarization of laurdan (GPL) of the nanoparticle is greater than or equal to about 0.6,
wherein the nanoparticle has a d-spacing of greater than about 6 nm or greater than about 7 nm, and
wherein at least 50%, at least 75%, at least 90%, or at least 95% of the nanoparticles have a surface fluidity value of greater than a threshold polarization level.
Although the references of record do not disclose the above limitations, the Examiner believes that given the correct analytical instrumentation and tagging experiment, that a skilled artisan (POSITA) would obtain these parameters under routine experimentation. The references of record have established all the instant claim limitations.
Regarding instant claim 62, Hahn et al., Cui et al., and Robinson et al. teach wherein the nanoparticle comprises about 30 mol% to about 60 mol% or about 40 mol% to about 50 mol% of ionizable lipid. Please see the discussion and citations within instant claim 5 for the necessary rejection text regarding the cationic lipid.
Regarding instant claim 64, Hahn et al., Cui et al., and Robinson et al. teach wherein the nanoparticle comprises about 5 mol% to about 15 mol%, about 8 mol% to about 13 mol%, or about 10 mol% to about 12 mol% of phospholipid. Please see the discussion and citations within instant claim 5 for the necessary rejection text regarding the phospholipid (fusogenic lipid).
Regarding instant claim 66, Hahn et al., Cui et al., and Robinson et al. teach wherein the nanoparticle comprises about 20 mol% to about 60 mol%, about 30 mol% to about 50 mol%, about 35 mol%, or about 40 mol% structural lipid. Please see the discussion and citations within instant claim 5 for the necessary rejection text regarding the structural lipid (cholesterol).
Regarding instant claim 74, Hahn et al., Cui et al., and Robinson et al. teach wherein the nanoparticle comprises about 1 mol% to about 5 mol% of PEG-lipid, or about 1 mol% to about 2.5 mol% of PEG-lipid. Please see the discussion and citations within instant claim 5 for the necessary rejection text regarding the PEG-lipid.
Regarding instant claim 75, Hahn et al., Cui et al., and Robinson et al. teach a cell comprising the nanoparticle of instant claim 1. Please see the discussion and citations within instant claims 3-4 and 15-17 for the necessary rejection text regarding a cell comprising the nanoparticle of instant claim 1.
Regarding instant claim 83, Hahn et al., Cui et al., and Robinson et al. teach a pharmaceutical composition comprising the nanoparticle of instant claim 1. Cui et al. disclose a carrier or excipient that is useful in preparing a pharmaceutical or therapeutic composition that is generally safe and non-toxic, and includes a carrier that is acceptable for veterinary and/or human pharmaceutical or therapeutic use. The terms "carrier" or "pharmaceutically acceptable carrier" can include, but are not limited to, phosphate buffered saline solution, water, emulsions (such as an oil/water or water/oil emulsion) and/or various types of wetting agents. As used herein, the term "carrier" encompasses, but is not limited to, any excipient, diluent, filler, salt, buffer, stabilizer, solubilizer, lipid, stabilizer, or other material well known in the art for use in pharmaceutical formulations…(see page 8, lines 21-29 within Cui et al.). Therefore, a skilled artisan (POSITA) could under routine experimental conditions prepare a pharmaceutical formulation/composition using the nanoparticle of instant claim 1.
Regarding instant claim 85, Hahn et al., Cui et al., and Robinson et al. teach wherein the composition is suitable for inhalation. Cui et al. disclose administration can be carried out by any suitable route, including oral, topical, intravenous, subcutaneous, transcutaneous, transdermal, intramuscular, intra-joint, parenteral, intra-arteriole, intradermal, intraventricular, intracranial, intraperitoneal, intralesional, intranasal, rectal, vaginal, by inhalation, via an implanted reservoir, parenteral
(e.g., subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intraperitoneal, intrahepatic, intralesional, and intracranial inj ections or infusion techniques), and the like…(see page 7, lines 24-30 within Cui et al.). Therefore, a skilled artisan (POSITA) could under routine experimental conditions prepare a pharmaceutical formulation/composition for inhalation using the nanoparticle of instant claim 1.
Regarding instant claim 120, Hahn et al., Cui et al., and Robinson et al. teach a method of delivering a polynucleotide or polypeptide payload into a cell comprising contacting the cell with a nanoparticle of instant claim 3, wherein the cell population is an epithelial cell population. Please see the discussion and citations within instant claim 1 for the necessary rejection text regarding the composition. Hahn et al. disclose a method for treatment using the nanoparticle (see claim 14 within Hahn et al.). In addition, Robinson et al. disclose where the cell population is an epithelial cell population (see abstract within Robinson et al.).
Combination of Hahn et al., Cui et al., Robinson et al., and Hassett et al.
Regarding instant claim 63, Hahn et al., Cui et al., Robinson et al., and Hassett et al. teach wherein ionizable lipid is:
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Hassett et al. disclose the ionizable lipid illustrated within instant claim 63 [see Fig. 3A (lipid M) within Hassett et al.]. Furthermore, Hassett et al. disclose that the ionizable lipid (lipid M) showed significantly more expression over time that of the most clinically advanced LNP (see page 2, 1st paragraph, left column; and page 4, 1st paragraph, right column; both within Hassett et al.). Therefore, a skilled artisan (POSITA) would be motivated to use this compound as an ionizable lipid.
Analogous Art
The Hahn et al., Cui et al., Robinson et al., and Hassett et al. references are directed to the same field of endeavor as the instant claims, that is, a nanoparticle comprising: (a) a lipid nanoparticle core comprising: (i) an ionizable lipid,(ii) a phospholipid,(iii) a structural lipid, and (iv) a PEG-lipid, and (b) a polynucleotide or polypeptide payload encapsulated within the core for delivery into a cell.
Obviousness
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the CSLN disclosed by Hahn et al., using the teachings of Cui et al., Robinson et al., and Hassett et al. to incorporate the necessary claim limitations.
The Hahn et al., Cui et al., Robinson et al., and Hassett et al. references all have considerable overlap with the use of a LNP encapsulating a nucleic acid (RNA). Therefore, a skilled artisan (POSITA) would be motivated to consult these citations.
Starting with Hahn et al., the skilled person only had to try the necessary claim limitations disclosed by Cui et al., Robinson et al., and Hassett et al. The combination of Hahn et al., Cui et al., Robinson et al., and Hassett et al. would allow one to arrive at the present application without employing inventive skill. This combination of the CSLN taught by Hahn et al. along with the use of the necessary claim limitations taught by Cui et al., Robinson et al., and Hassett et al. would allow a research and development scientist (POSITA) to develop the invention taught in the instant application.
It would have only required routine experimentation to modify the CSLN disclosed by Hahn et al. with the use of the necessary claim limitations taught by Cui et al., Robinson et al., and Hassett et al. This combined modification would have led to an enhanced LNP containing a cationic lipid that would be beneficial for patients.
In the context of instant method claim 120 the desired purpose defines an effect that arises from and is implicit in the method step(s). Thus, where the purpose is limited to stating a technical effect that inevitably occurs during the performance of the claimed method step(s), and is therefore inherent in that/those step(s), that technical effect is not limiting to the subject-matter of the claim. Thus, the present method claim, defining the application/use of the composition according to the prior art, and defining its purpose as "use", is anticipated by any document of the state of the art describing a method of application/use although not mentioning this specific use.
Response to Arguments
Applicant's arguments filed February 17, 2026 have been fully considered but they are not persuasive.
The instant claim amendments were sufficient to address the claim objections. Additionally, the arguments within the Remarks section of the response were sufficient to address the Statutory Double Patenting rejection. Therefore, they are both withdrawn from the non-final office action dated November 17, 2025.
The amendments did not necessitate a new ground of rejection.
Applicant Argument: The Applicant argues that the Hahn et al. reference does not disclose the encapsulation of the nucleic acid within the core.
Examiner’s Rebuttal: The Examiner respectfully disagrees. Yes, paragraph [0033] within Hahn et al. does disclose, “[t]he nanoparticles of the present invention may bind with drugs, particularly anionic drugs and/ or nucleic acid genes by electrostatic interaction through the exposed cationic lipids of the shell, thus easily forming a complex, and it may be usefully used as a composition for intracellular delivery of drugs, particularly anionic drugs and/or nucleic acid genes.” However, there is significant debate of the defined structures of LNPs. “The drug encapsulation and delivery properties can be assumed to be dependent on the exact structure of the LNP, but due to their complexity, there is currently no clear model for LNP structures” (see pages 2073-2074 bridging within PTO-892 NPL X). Three models for self-assembled particles have been proposed within the literature (see page 2074 within PTO-892 NPL X; Figure I).
Figure I
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Therefore, indicating to the Examiner that no clear well-defined structure is known and accepted. The Applicant’s claimed encapsulation of the polynucleotide is in question. The Applicant is requested to present evidence supporting this claim.
Applicant Argument: The Applicant argues that the LNP of instant claim 1 provides unexpected results.
Examiner’s Rebuttal: The Examiner respectfully disagrees. The Examiner has found no comparative data (closest prior art) within the instant specification. Furthermore, the Robinson et al. reference discloses similar results with cystic fibrosis as described above within instant claims 3-4 and 15-17. Moreover, evidence of unexpected results must be weighed against evidence supporting prima facie obviousness in making a final determination of the obviousness of the claimed invention. In re May, 574 F.2d 1082, 197 USPQ 601 (CCPA 1978) (Claims directed to a method of effecting analgesia without producing physical dependence by administering the levo isomer of a compound having a certain chemical structure were rejected as obvious over the prior art. Evidence that the compound was unexpectedly nonaddictive was sufficient to overcome the obviousness rejection. Although the compound also had the expected result of potent analgesia, there was evidence of record showing that the goal of research in this area was to produce an analgesic compound which was nonaddictive, enhancing the evidentiary value of the showing of nonaddictiveness as an indicium of nonobviousness.). [see M.P.E.P. 716.02(c)]. In this instance, the prior art of record is stronger than the unexpected results. The prima facie case for obviousness presented within the 35 U.S.C. §103 section of this office action affords a “direct pathway” of research for a skilled artisan (POSITA) to develop and obtain similar results as observed by the inventors.
Applicant Argument: The Applicant argues that the Cui et al. reference supplies no specific examples having the necessary zeta potential.
Examiner’s Rebuttal: Despite this fact, Cui et al. is not required to disclose specific examples of every zeta potential. The range is supported within the specification. A skilled artisan (POSITA) could modify the PEG-lipid, cationic lipid (molar ratio/structure), and pH to be within the zeta potential range.
Applicant Argument: The Applicant argues that the Office uses piece-meal from Han et al. and Cui et al. to teach many of the elements of instant claim 1.
Examiner’s Rebuttal: The Examiner respectfully disagrees. It must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight or piece-meal reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Thus, the 35 U.S.C. §103 rejection for instant claims 1, 3-17, 62-64, 66, 74-75, 83, 85 and 120 is maintained.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/JOHN W LIPPERT III/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615
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