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 .
Claim Interpretation
Claim 1 recites that the solid formulation comprises an opioid antagonist and one or more of a binder, a stabilizing excipient, and a lubricant. Under the broadest reasonable interpretation, the Examiner interprets such limitation to mean that the solid formulation comprises an opioid antagonist and one or more chosen from a binder, a stabilizing excipient or a lubricant.
Claim Objections
Claim 1 is objected to because of the following informalities: on lines 6-7, applicant need to change “one or more of a binder, a stabilizing excipient, and a lubricant,” to --- one or more chosen from a binder, a stabilizing excipient, or a lubricant, --- to make the meaning of the claim clearer (unless applicant meant that the solid formulation comprises one or more of a binder, one or more of a stabilizing excipient and one or more of a lubricant). Appropriate correction is required.
Claim 5 is objected to because of the following informalities: on line 2, applicant need to change “and a rod” to --- or a rod ---. Appropriate correction is required.
Claim 10 is objected to because of the following informalities: on line 4, applicant need to change “and an antioxidant” to --- or an antioxidant ---. Appropriate correction is required.
Claim 41 is objected to because of the following informalities: on line 3 applicant need to change “and butylated” to --- or butylated ---. Appropriate correction is required.
Claim 33 is objected to because of the following informalities: on the last line, applicant need to delete “between”. Appropriate correction is required.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim(s) 1, 5-8, 11, 21, 26, 29 and 42 are rejected under 35 U.S.C. 103 as being unpatentable over Watkins (WO 2019/168985 A1).
Watkins teaches ([0057], [0058] and [0156]) a subcutaneous implantable device for delivery of a composition or aqueous suspension of small molecule therapeutic agent and an organic acid. In Fig. 1A and Fig.1B (see also [0158]), Watkins provide illustrations of its drug delivery device that is assembled and ready for implantation in an anatomical compartment of a subject, such as under the skin or in the peritoneal cavity. The housing comprises an non-erodible housing member that defines an internal reservoir. Contained within the internal reservoir is the composition of the therapeutic agent and an organic acid. The housing member has first and second ends. The first end is sealed with a fluid-tight end cap that can comprise a porous partition. The second end is fitted with a porous partition. In its Example 8 ([0210]), Watkins teaches that various salts of naltrexone were prepared and formed into tablets and filled into the (internal) reservoir of its drug delivery device. Watkins further teaches that the loaded devices were hydrated and placed into PBS (phosphate buffered saline) at 37oC on a planetary rotator and aliquots of receiving buffer were analyzed for naltrexone concentration. Thus, Watkins teaches instant device for delivery of an opioid antagonist (instant pharmaceutically acceptable salt of naltrexone) comprising a device an interior reservoir with an inner diameter, first end, a second end, and a porous partition, the device dimensioned for subcutaneous implantation into a subject, wherein the compressed shape (instant tablet of claim 5) when hydrated forms an aqueous phase in the interior reservoir of the device, the aqueous phase comprising dissolved opioid antagonist that is released from the device by diffusion across the porous partition for a period of at least about one month (Watkins teaches (see Fig.10A) that the naltrexone salts are delivered for a period of at least 80 days).
With respect to instant limitation “one or more of a binder, a stabilizing excipient, or a lubricant”, Watkins teaches ([0199] and [021]) that its naltrexone salt is mixed with polyvinylpyrrolidone (instant binder of claims 7 and 8) as a binding agent and stearic acid (instant lubricant of claim 42) as a lubricant before being pressed into a tablet form.
With respect to instant limitation as to the solid formulation in the form of a compressed shape with a diameter equal to or greater than 80% of the inner diameter of the interior reservoir, Watkins teaches ([0199]) that dies used for tableting had diameters matched to the internal diameters of the device reservoirs. This implies that the diameter of Watkins’s tablet would be close to the inner diameter of the device reservoir, thus impliedly teaching instant limitation as to the diameter of the compressed shape being equal to or greater than 80% (or 90% as claimed in instant claim 6) of the inner diameter of the device reservoir. Alternatively, under the guideline given by Watkins, instant range of claim 1 (equal to or greater than 80% of the inner diameter of the interior reservoir) as well as instant range of claim 6 (equal to or greater than 90% of the inner diameter of the interior reservoir) for the diameter of the compressed shape would have been obvious to one skilled in the art before the effective filing date of the claimed invention since it has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. In re Aller, 105 USPQ 233.
Thus, Watkins renders obvious instant claims 1, 5-8, 21 and 42.
With respect to instant claim 11, Watkins’s composition formed into tablets comprises instant naltrexone salt, instant binder of claims 7-8 and instant lubricant of claim 42. Thus, Watkins’s tablet (instant solid formulation) would naturally have a melting point greater or equal to about 40oC (besides, Watkins also teaches (claim 5) that the organic acid (which is contained in Watkins’s naltrexone salt composition) has a melting temperature of more than about 37oC). Thus, Watkins renders obvious instant claim 11.
With respect to instant claim 26, Watkins teaches ([0067], [0192], [0193]) a method for sustained, controlled delivery of a small molecule therapeutic agent (such as naltrexone salt) wherein the therapeutic plasma level of the therapeutic agent is maintained for at least 4 weeks. Thus, Watkins renders obvious instant claim 26.
With respect to instant claim 29, as already discussed above, Watkins’s device is implanted under the skin or in the peritoneal cavity of a subject. Watkins further teaches ([0061]) that its formulation is hydrated in the presence of an aqueous solution to form an aqueous suspension (prior to implanting the device) or hydrated in the presence of an aqueous solution which is in vivo fluid. Thus, Watkins renders obvious instant claim 29.
Claim(s) 10 and 39-41 are rejected under 35 U.S.C. 103 as being unpatentable over Watkins (WO 2019/168985 A1) in view of Pavlovich (WO 2018/191430 A1).
Watkins does not explicitly teach the use of instant stabilizing excipient. Pavlovich teaches ([0210]-[0211]) that adding ascorbic acid (instant antioxidants of claims 10 and 41) to a naltrexone pellet (further comprising povidone and stearic acid – see [0201]-[0204]) made the pellets less fragile and reduce the amount of naltrexone that oxidized (as verified by potency tests). It would have been obvious to one skilled in the art to further add ascorbic acid to Watkins’s naltrexone salt formulation with a reasonable expectation of making the formed tablets less fragile and reducing the amount of naltrexone that oxidizes. Thus, Watkins in view of Pavlovich renders obvious instant claims 10 and 39-41 (current claim languages of claims 39 and 40 do not require the presence of the metal chelating agent and the buffering agent, respectively. They only require that if the metal chelating agent is present, then the metal chelating agent has to be ethylenediaminetetraacetic acid and that if the buffering agent is present, then the buffering agent has to be selected from a phosphate salt, carboxylate salt or amino acid).
Claim(s) 33 is rejected under 35 U.S.C. 103 as being unpatentable over Watkins (WO 2019/168985 A1) in view of Younger et al (“The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain”, Clin Rheumatol, vol.33 (2014), pg.451-459).
As already discussed above, Watkins’s device is implanted under the skin or in the peritoneal cavity of a subject. Thus, Watkins teaches instant steps of providing a device according to claim 1 and administering the device to a human subject by subcutaneous implantation. As to instant limitation “whereby said administering provides delivery of the opioid antagonist in an amount that provides a therapeutic blood level for a period of about 1-36 months”, as already discussed above, Watkins teaches ([0067], [0192], [0193]) a method for sustained, controlled delivery of a small molecule therapeutic agent (such as naltrexone salt) wherein the therapeutic plasma level of the therapeutic agent is maintained for at least 4 weeks. Such range overlaps with instant range about 1-36 months, thus rendering instant range prima facie obvious. In the case “where the [claimed] ranges overlap or lie inside ranges disclosed by the prior art,” a prima facie case of obviousness would exist which may be overcome by a showing of unexpected results, In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976). Although Watkins does not explicitly teach that its implanted device containing its naltrexone formulation is used for treating an inflammatory, neuroinflammatory or metabolic disorder, as evidenced by Younger et al (see abstract), low-dose naltrexone (LDN) has been demonstrated to reduce the symptom severity in conditions, such as fibromyalgia, Crohn’s disease, multiple sclerosis and complex regional pain syndrome (all of which are inflammatory, neuroinflammatory or metabolic disorders). Younger further teaches (abstract) that daily dose of LDN is inexpensive and well-tolerated. It would have been obvious to one skilled in the art to (subcutaneously) implant Watkins’s device containing naltrexone formulation into a subject suffering from conditions, such as fibromyalgia, Crohn’s disease, multiple sclerosis and complex regional pain syndrome, so as to be able to provide low-dose naltrexone(LDN) continuously over a period of at least 4 weeks with a reasonable expectation of success. Thus, Watkins in view of Younger renders obvious instant claim 33.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SIN J. LEE whose telephone number is (571)272-1333. The examiner can normally be reached on M-F 9 am-5:30pm.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Brian Kwon can be reached on 571-272-0581. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SIN J LEE/
Primary Examiner, Art Unit 1613
July 25, 2026
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