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 .
DETAILED ACTION
Claim Status
Claims 1-17 and 26-30 are pending. Claims 26-30 have been added. Claims 18-25 have been canceled. Claims 7-8, 10, 12-13, 15-16 and 26-30 are being examined in this application. In response to the restriction requirement, Applicants elected morphine, Tyr-c[D-Lys-Trp-Phe-Glu]-Gly-NH2 (ZH853), and wherein the subject has not been treated previously with another agent. Claims 1-6, 9, 11, 14 and 17 are withdrawn as being drawn to a nonelected species.
Claim Rejections - 35 USC § 112
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.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
This is a new rejection.
Claim 28 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 28 is drawn to “wherein the pharmaceutical composition is initially administered at a dose of 0.3 mg/kg to 3.2 mg/kg of the peptide of Formula II”. This is indefinite. To advance prosecution, the claim has been interpreted as being drawn to “The method of claim 7, wherein the pharmaceutical composition is initially administered at a dose of 0.3 mg/kg to 3.2 mg/kg of the peptide of Formula II”.
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.
This rejection has been modified.
Claims 7-8, 10, 12-13, 15 and 26 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Zadina et al. (US 2017/0369531).
With respect to claims 7-8, 10, 12 and 26, Zadina et al. teach a method for providing analgesia, providing relief from a gastrointestinal disorder, or providing therapy for a drug dependence comprising administering to a patient an effective amount of a cyclic peptide of formula I (H-Z-c[X1-X2-X3-X4]-X5) (claim 11), wherein the patient has a history of substance abuse (claim 14).
Zadina et al. also teach that “[B]eyond the value of high mu agonist selectivity (i.e., exclusion of potential side-effects resulting from activation of multiple receptors), delta antagonism is expected to attenuate opioid-induced tolerance, dependence, and reward. As first shown in 1991 and supported in numerous studies since, delta antagonists can reduce morphine induced tolerance and dependence, while maintaining or enhancing analgesia. Recent studies have also shown reduced rewarding properties of mu agonist/delta antagonists as reflected in the conditioned place preference (CPP) test described below. The activity of the peptides of Formula I (e.g., Compound 1) as mu agonists/delta antagonists as well as at mu/delta receptor dimers indicate that the peptides will produce effective analgesia with reduced tolerance, dependence, and reward” (para [0068]).
Zadina et al. further teach that “[E]xplanations for the tolerance and opioid induced hypersensitivity include the possibility that activation of glia, a reflection of an inflammatory response, results in an increased release of substances that activate or sensitize neuronal transmission of nociceptive signals. Specifically, enhanced release of "pronociceptive" cytokines and chemokines are thought to mediate the enhanced pain sensitivity sometimes observed after chronic exposure to opioids. In addition, several studies have linked this phenomenon to opioid tolerance based on the concept that increasing doses of opioids are required to overcome the increased pronociceptive effects of the released compounds. Described below are the unexpected findings that: (1) Compounds 1, 2 and 5 produce significantly less tolerance relative to morphine, and (2) in direct comparison to morphine, and in contrast to morphine and most clinically used opioids, the analogs do not induce an inflammatory glial activation response after chronic administration” (para [0078]).
Zadina et al. additionally teach that the peptide is Tyr-c[D-Lys-Trp-Phe-Glu]-Gly-NH2 (SEQ ID NO: 3) (para [0017]), which corresponds to the elected species.
With respect to the claimed “discontinued chronic exposure to an opioid”, it is noted that any subject using opioids must necessarily discontinue exposure between one dose and another.
Therefore, since Zadina et al. teach administering the instantly claimed peptide for the treatment of subjects with chronic exposure to opioids, the withdrawal symptoms associated with said exposure to opioids would inherently be prevented (see MPEP 2112.01).
With respect to claim 13, Zadina et al. teach that the mu opioid receptor agonist is morphine (paras [0075]-[0076]; passim).
With respect to claim 15, Zadina et al. teach that the peptide is administered intravenously (paras [0019], [0049], [0069] and [0072]).
Response to Arguments
Applicant’s arguments filed on 8/19/2026 have been fully considered but they are not persuasive.
Applicant argues that “[A] claim is anticipated only if each and every element as set forth in the claim is found, either expressly or inherently described, in a single prior art reference." MPEP § 2131 citing Verdegaal Bros. v. Union Oil Co. of California, 814 F .2d 628, 631, 2 USPQ2d 1051, 1053 (Fed. Cir. 1987). Regarding inherency, the Office must identify some basis in fact or articulate some reasoning at least tending to show that allegedly inherent subject matter necessarily (i.e., inevitably) flows from cited art. "The fact that a certain result or characteristic may occur or be present in the prior art is not sufficient to establish the inherency of that result or characteristic." MPEP § 2112(IV) citing In re Rijckaert, 9 F.3d 1531, 1534, 28 USPQ2d 1955, 1957 (Fed. Cir. 1993) (emphasis added). "To establish inherency, the extrinsic evidence 'must make clear that the missing descriptive matter is necessarily present in the thing described in the reference, and that it would be so recognized by persons of ordinary skill. Inherency, however, may not be established by probabilities or possibilities. The mere fact that a certain thing may result from a given set of circumstances is not sufficient."' MPEP § 2 l 12(IV) citing In re Robertson, 169 F.3d 743, 745, 49 USPQ2d 1949, 1950-51 (Fed. Cir. 1999) (emphasis added). "'In relying upon the theory of inherency, the examiner must provide a basis in fact and/or technical reasoning to reasonably support the determination that the allegedly inherent characteristic necessarily flows from the teachings of the applied prior art."' MPEP § 2112(IV) citing Ex parte Levy, 17 USPQ2d 1461, 1464 (Bd. Pat. App. & Inter. 1990). Zadina does not disclose, either expressly or inherently, that administration of the peptides disclosed therein would prevent withdrawal symptoms induced by discontinued chronic exposure1 to an opioid. Instead, Zadina merely discloses particular cyclic peptide agonists for use in the treatment of acute and/or chronic pain (Zadina, Abstract). Indeed, Zadina fails to disclose providing the peptides disclosed therein to any subject after chronic exposure to an opioid. The Office Action's reliance on Zadina' s disclosure that "enhanced release of 'pronociceptive' cytokines and chemokines are thought to mediate the enhanced pain sensitivity sometimes observed after chronic exposure to opioids" as equating to administering the peptides of the current claims to subjects after chronic exposure to opioids is both flawed and unsubstantiated. Indeed, Zadina speculates (i.e., is "thought to") that the cytokine/chemokine release mechanism possibly (i.e., "sometimes") mediates pain sensitivity and does not constitute a disclosure to actively administer the claimed peptides to subjects who discontinued chronic exposure to an opioid, let alone for the purpose of preventing withdrawal symptoms induced by said discontinued chronic opioid exposure. As discussed above, the MPEP explicitly states that inherency "may not be established by probabilities or possibilities," therefore prohibiting the Office's reliance on Zadina' s speculation regarding a cytokine/chemokine release mechanism for the purposes of a rejection under 35 U.S.C. § 102. See MPEP § 2112(IV). Because Zadina fails to disclose each and every limitation of the currently pending claims, the rejection under 35 U.S.C. §102 is improper and should be withdrawn”.
Applicant’s arguments are not persuasive.
The MPEP 2112.02 II states that “[w]hen the claim recites using an old composition or structure and the "use" is directed to a result or property of that composition or structure, then the claim is anticipated. In re May, 574 F.2d 1082, 1090, 197 USPQ 601, 607 (CCPA 1978) (Claims 1 and 6, directed to a method of effecting nonaddictive analgesia (pain reduction) in animals, were found to be anticipated by the applied prior art which disclosed the same compounds, as well as a method of using them for effecting analgesia but which was silent as to addiction. The court upheld the rejection and stated that the inventors had merely found a new property of the compound and such a discovery did not constitute a new use. The court went on to reverse the obviousness rejection of claims 2-5 and 7-10 which recited a process of using a new compound. The court relied on evidence showing that the nonaddictive property of the new compound was unexpected.). See also In re Tomlinson, 363 F.2d 928, 150 USPQ 623 (CCPA 1966) (The claim was directed to a process of inhibiting light degradation of polypropylene by mixing it with one of a genus of compounds, including nickel dithiocarbamate. A reference taught mixing polypropylene with nickel dithiocarbamate to lower heat degradation. The court held that the claims read on the obvious process of mixing polypropylene with the nickel dithiocarbamate and that the preamble of the claim was merely directed to the result of mixing the two materials. "While the references do not show a specific recognition of that result, its discovery by appellants is tantamount only to finding a property in the old composition." 363 F.2d at 934, 150 USPQ at 628 (emphasis in original))”.
In the instant case, the claims recite using an old composition (i.e. a pharmaceutical composition comprising the peptide of Formula II) and the "use" is directed to a result or property of that composition (i.e. prevention of withdrawal symptoms). Therefore, the claims are anticipated.
For the reasons stated above the rejection is maintained.
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.
This rejection has been modified.
Claims 7-8, 10, 12-13, 15-16 and 26-30 are rejected under 35 U.S.C. 103 as being unpatentable over Zadina et al. (US 2017/0369531).
The teachings of Zadina et al. with respect to claims 7-8, 10, 12-13, 15 and 26 have been discussed above.
Zadina et al. do not teach the doses claimed in instant claims 16 and 28-29.
Please note that the instant specification teaches that “[T]he term "analgesic ED50", as used herein with respect to a peptide of Formula I, refers to a dose of the peptide which provides 50% analgesia as determined for alleviation of intradermal capsaicin-induced pain by the Dixon sequential up-down method (see, e.g., Wong 2014). The analgesic ED50 dose may be different for different methods of administration (e.g., oral, intravenous, intrathecal, subcutaneous, transdermal, and the like), as is well known in the pharmaceutical arts. In rats, a suitable model for determining a dose response curve and an ED50 for antinociception (an animal model for analgesia) is the tail flick test (see Zadina 2016). Based on tail flick studies, the antinociceptive ED50 for ZH853 in rats is about 2 mg/Kg” (para [0053]).
Therefore, instant claim 16 relates to a dose of about 1 mg/Kg.
However, Zadina et al. teach that the dosage of the effective amount of the peptides can vary depending upon the age and condition of each individual patient to be treated. However, suitable unit dosages typically range from about 0.01 to about 100 mg (para [0058]).
A prima facie case of obviousness necessarily exists when the prior art range overlaps or touches a claimed range, such as in the instant rejection (MPEP § 2144.05).
Furthermore, the MPEP 2144.05 A states that “[G]enerally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[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) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Laboratories Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In re Kulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997)”.
Since Applicant has not disclosed that the specific limitations recited in the instant claims are for any particular purpose or solve any stated problem, absent unexpected results, it would have been obvious for one of ordinary skill to discover the optimum dosage by normal optimization procedures known in the pharmaceutical art.
Similarly, with respect to claims 27 and 30, the skilled artisan would have been motivated to treat opioid use disorder in subjects regardless of the daily exposure to an opioid and regardless of the time in which the exposure was discontinued.
Response to Arguments
Applicant’s arguments filed on 8/19/2026 have been fully considered but they are not persuasive.
Applicant argues that “[Z]adina fails to provide a person of ordinary skill in the art ("POSITA") with the motivation or a reasonable expectation in administering the peptides of Applicant's present claims to prevent withdrawal symptoms induced by discontinued chronic exposure to an opioid. Instead, Zadina teaches that cyclic peptide agonists may be used for "use in the treatment of acute and/or chronic pain." Zadina, Abstract. Zadina fails to teach or suggest that the peptide agonists may be used to prevent withdrawal symptoms induced by discontinued chronic exposure to an opioid, and the Office Action instead concludes that by administering the peptide agonists that "the withdrawal symptoms associated with said exposure to opioids would inherently be prevented." Office Action at pp. 4-5”.
Applicant also argues that “[t]he skilled artisan at the time of filing would have appreciated that not all opioid agonists are capable of preventing withdrawal symptoms induced by discontinued chronic opioid exposure. Accordingly, absent experimental evidence to the contrary, the skilled artisan could not have reasonably predicted which opioid agonists could be used to successfully prevent withdrawal symptoms induced by discontinued chronic opioid exposure. In contrast, FIG. 10 of the instant application (reproduced below) demonstrates that the claimed opioid agonist effectively blocks withdrawal symptoms induced by discontinued chronic exposure to morphine, as evidenced by significantly lower Global Withdrawal Scores (GWS) and Wet Dog Shakes (WDS) compared to vehicle controls.
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The teachings of Zadina fail to render the pending claims obvious because Zadina does not teach or suggest each and every element of the claims, and also fails to provide any rationale or motivation for a skilled artisan to combine or modify the teachings therein to arrive at the claimed subject matter with any reasonable expectation of success”.
Applicant’s arguments are not persuasive.
Applicant’s arguments have been addressed above under “Response to Arguments” on pages 5-8.
With respect to Applicant’s arguments regarding Fig. 10, as discussed above, the claims recite using an old composition (i.e. a pharmaceutical composition comprising the peptide of Formula II) and the "use" is directed to a result or property of that composition (i.e. prevention of withdrawal symptoms).
For the reasons stated above the rejection is maintained.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SERGIO COFFA whose telephone number is (571)270-3022. The examiner can normally be reached M-F: 6AM-4PM.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, MELISSA FISHER can be reached at 571-270-7430. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SERGIO COFFA Ph.D./
Primary Examiner
Art Unit 1658
/SERGIO COFFA/Primary Examiner, Art Unit 1658
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