DETAILED ACTION
Claims 1-9 are pending in the instant application.
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 .
Priority
The instant application claims priority to 371 of PCT/CN2023/072651 filed 01/17/2023 which claims priority to CHINA 202210113469.0 filed on 01/30/2022.
Information Disclosure Statement
The information disclosure statement (IDS) is in compliance with the provisions of 37 CFR 1.97, except where noted. Accordingly, the information disclosure statement was considered by the examiner. Please see attached initialed Forms 1449.
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.
Claims 1-9 are rejected under 35 U.S.C. 103 as being unpatentable over Lee et al. (WO 1996/40060), Stein et al. (US 2014/0228406 A1), Brigham et al. (Degradable polymeric vehicles for postoperative pain management, nature communications, 2021), and Burgess (Liposome Preparation – Avanti Research, 2001).
Lee discloses improved liposomes for facilitating the delivery of extracellular agents (pg 2, middle paragraph). The liposomes are pH-sensitive liposomes. In general, liposomes formed of oleic acid and phosphatidylethanolamine are pH-sensitive liposomes (pg 3, middle paragraph). Liposomes are used to deliver analgesic (pg 14). Liposomes are prepared at neutral pH or in accordance with procedures known to one of ordinary skill in the art; this includes dissolving phospholipid and cholesterol in organic solvent. The method also includes hydrating lipids (pg 19, General Protocol).
Lee does not explicitly mention peripheral nerve injury and dorsal root ganglion.
Stein discloses fentanyl derivatives that function as opioid receptor agonists, which activate target opioid receptors in a pH-dependent manner, and are thus selective for the receptors in inflamed milieu (Abstract). There is need of development of new generations and formulations of opioids which are devoid of side effects – this can be achieved by targeting opioid receptors on peripheral terminals of dorsal root ganglion neurons ([0004]). The composition containing the active ingredient may be in a form of liposomes ([0040]). Stein discloses Mu-opioid receptor (Example 3).
Brigham discloses that the implementation of a device that safely and reliably provides extended analgesia is needed (Abstract). Not only does the composition of the API effect the overall impact of the device, but the manner in which the API is embedded into the device also plays a significant role. An important design element in controlled drug delivery devices is drug incorporation through physical or chemical means. The synthetic nature of most polymers affords the ability of drug to be linked onto the polymer backbone upon synthesis and later to be cleaved hydrolytically or by other methods77. As one could imagine, release from these devices is dependent upon the cleavage of built-in labile bonds to release the therapeutic molecule. Physically imbedded drug, on the other hand, can be mixed into the system and held in place by intermolecular forces (i.e., ionic, hydrogen bonding) or steric interactions. In these systems, energetic considerations of the environment are important, including the release media, physical agitation, temperature, and pH used to promote the diffusion of the drug out of the matrix. Importantly, at the site of tissue injury, the pro-inflammatory environments have lower pH due to increased proton levels and acidosis, which will have an impact on the API elution; low pH is a hallmark of injured tissue. Some drugs show pH-sensitive binding to their targets. For example, a nontoxic pain killer has been developed to activate peripheral μ-opioid receptors (pg 5, right col, last paragraph).
Burgess discloses thin-lipid film method of creating liposomes (pg 1). Burgess discloses that lipids are dissolved in organic solvent first (pg 2). Then solvent is evaporated. The lipid film is dried by vacuum (pg 3). Burgess discloses that hydration is accomplished by simply adding an aqueous medium to the container of dry lipid and agitating (pg 4). Burgess discloses that hydration time may differ slightly among lipid species and structure (pg 5, 1st paragraph). Burgess discloses extruding the lipid suspension (pg 6).
Therefore, it would have been obvious to one of ordinary person in the art before the effective filing date of the claimed invention to have combined teachings of above to create a pH-sensitive liposome targeting the dorsal root ganglion. This is taking some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Regarding claim 2, phosphatidylethanolamine (PE) and oleic acid are discussed above.
Regarding claim 3, mu opioid receptor is taught above.
Regarding claim 4, one of ordinary skill in the art would contemplate embedding the active ingredient within the liposome itself as taught by Brigham.
Regarding claim 5, Lee discloses that the liposome formulation further includes extracellular agents (analgesics) in the hydration phase for entrapping such agents in the liposomes for delivery. To one of ordinary skill in the art, the exemplary procedure can be modified using no more than routine skill and experimentation to form pH-sensitive and pH-insensitive liposomes (pg 21, last paragraph). Additionally, Lee discloses hydrating lipids (liposome hydration method or thin-film hydration method) (pg 19, Lee mentions hydrating lipids). One of ordinary skill in the art would routinely utilize procedures already known to create pH-sensitive liposomes. Claim 5 of instant application describes the method of thin-film hydration. Burgess teaches the thin-film method of creating liposomes.
Regarding claim 6, Lee discloses that the pH-sensitive lipids contain about in an amount of about 50% to 100% of phosphatidylethanolamine with oleic acid in an amount of about 0 to 50% (pg 8, 1st paragraph). One of ordinary skill in the art would immediately envisage that it would be routine practice to create liposomes with various molar ratios of PE to oleic acid.
Regarding claim 7, as Burgess disclosed, one of ordinary skill in the art would routinely experiment with different hydration times depending on the lipid species and structure.
Regarding claim 8, a pH-sensitive liposome comprising an analgesic that can target pain receptors in the dorsal root ganglion would be used for treatment of neuropathic pain.
Regarding claim 9, the injured tissue has a local acidic environment and a pH-sensitive liposome would inherently offload active ingredient within these sites.
Conclusion
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/JOHN SEUNGJAI KWON/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615
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