DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Response to Amendment
2. Applicant's amendment and response, submitted September 12, 2025 as been reviewed by the examiner and entered of record in the file.
3. Claims 40-42 are newly added. No claim is amended or canceled.
4. Claims 21-42 are under examination and are the subject of this office action.
Claim Rejections - 35 USC § 103
5. The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
6. Claims 21-34, 36 and 38 remain rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Gillin et al., (“Rebound Insomnia: A Critical Review,” 1989), in view of Kavey et al., (U.S. Pat. No. 5,643,897 A1), and in view of Hajak et al., (J. Clin. Psychiatry 2001).
Claim 21 is directed to a method of treating sleep maintenance insomnia in a patient suffering from sleep maintenance insomnia (claim 29) and at risk of rebound insomnia, comprising:
(1) identifying a patient suffering from sleep maintenance insomnia,
(2) determining that the patient is at risk of rebound insomnia based on a history of rebound insomnia while taking one or more non-doxepin sleep medications (more specifically, a benzodiazepine (claim 34)),
providing information to the patient that between about 1 mg and about 6 mg of doxepin is effective to treat the sleep maintenance insomnia and does not cause rebound insomnia resulting from the treatment even upon abrupt discontinuation;
(3) administering doxepin or a salt thereof to a patient, based on the determination that the patient is at risk of rebound insomnia and the information that doxepin is effective to treat the sleep maintenance insomnia and does not cause rebound insomnia resulting from the treatment even upon abrupt discontinuation, wherein the daily dosage of doxepin is between about 1 mg and about 6 mg, (more specifically about 3 mg (claim 23) or about 6 mg (claim 24)); and
(4) discontinuing the administration of doxepin for a discontinuation period of at least two days, wherein the patient does not have rebound insomnia during the discontinuation period.
Claim 25, as amended, is directed to a method of treating insomnia in a patient without causing rebound insomnia even upon abrupt discontinuation of the treatment, the method comprising:
(1) identifying a patient using one or more non-doxepin sleep medications (more specifically a benzodiazepine (claim 36)), for the treatment of insomnia;
(2) determining that the patient is at risk of rebound insomnia, discontinuing the patient’s use of non-doxepin sleep medication;
(3) administering doxepin or a salt thereof to a patient, based on the doxepin or salt thereof being effective to treat the insomnia without causing rebound insomnia resulting from the treatment even upon abrupt discontinuation, wherein the daily dosage of doxepin is between about 1 mg and about 6 mg, more specifically about 3 mg (claim 27) or about 6 mg (claim 28); and
(4) discontinuing the administration of doxepin for a discontinuation period of at least two days, wherein the patient does not have rebound insomnia during the discontinuation period.
Claim 30, as amended, is directed to a method of treating sleep maintenance insomnia, comprising:
(1) identifying a patient using one or more non-doxepin sleep medications (more specifically a benzodiazepine (claim 38)), for the treatment of insomnia, wherein the non-doxepin sleep medication has rebound insomnia as a potential side effect,
(2) discontinuing the patient’s use of the non-doxepin sleep medication,
providing information to the patient indicating that rebound insomnia is not a side effect with the use of 1 mg and about 6 mg of doxepin for the treatment of sleep maintenance insomnia even upon abrupt discontinuation;
(3) selecting a doxepin therapy protocol for treating the patient’s sleep maintenance insomnia, wherein the daily dosage of doxepin is between about 1 mg and about 6 mg, (more specifically about 3 mg (claim 32) or about 6 mg (claim 33)); and
(4) discontinuing the administration of doxepin for a discontinuation period of at least two days, wherein the patient does not have rebound insomnia during the discontinuation period.
7. Gillin et al. teach that the administration of a non-doxepin sleep medication (benzodiazepine) to insomniac patients results in rebound insomnia:
“a worsening of sleep compared to pretreatment levels, has been reported upon discontinuation of short half-life benzodiazepine hypnotics,” (see page 2, first paragraph under “Summary”).
8. Thus, a medical practitioner would necessarily consider that a patient suffering from sleep maintenance insomnia with a history of taking one or more non-doxepin sleep medications for insomnia (specifically a benzodiazepine), resulting in rebound insomnia, is at risk of rebound insomnia. Gillin et al. are silent to the administration of doxepin.
9. Yet, Kavey et al. discuss the treatment of sleep maintenance insomnia in an adult patient who had been previously treated with the benzodiazepine hypnotic alprazolam “without improvement,” wherein said patient “was started on doxepin 5 mg which produced a clinical cure. After two years at this dosage, he continues to sleep well and has experienced no adverse effects from the medication,” [emphasis added] (see column 4, Example 6). The dosage of 5 mg employed by Kavey et al. is within the range of “between about 1 mg to about 6 mg,” required by instant claims 21, 25 and 30.
10. And, Hajak et al. teach a polysomnographic study demonstrating the effects of administering either doxepin or placebo to groups of insomniac patients for a period of 28 nights, followed by an abrupt discontinuation period of 2 weeks, (page 454, right column, Figure 1). Hajak et al. observed that:
“[d]oxepin did not cause rebound insomnia when rebound in polysomnographic sleep parameters was analyzed according to standard methods… Changes in mean values of sleep parameters before and after treatment were not significantly different between treatment groups…. Since mean changes from baseline values often failed to reflect the occurrence of rebound insomnia, we also calculated the number of patients with rebound (i.e., the rebound rate) for those sleep parameters that showed significant effects during the treatment period. We found that neither the rebound rate for at least 1 of the rebound sleep parameters nor the amount of rebound (in the patients having rebound) differed significantly between the treatment groups,”
(page 461, left column, last paragraph- right column, first paragraph).
11. As such, one skilled in the art would have a reasonable expectation of successfully treating sleep maintenance insomnia in a patient in need thereof by administering a low therapeutic dose of doxepin, wherein said patient is at risk of rebound insomnia based on a history of rebound insomnia while taking one or more non-doxepin sleep medications (specifically, a benzodiazepine),. One skilled in the art would be motivated to switch sleep medications to low dose doxepin in view of the teaching of Kavey et al.: low dose doxepin results in no incidence or very low incidence of adverse effects, (e.g., rebound insomnia), and Hajak et al.: following a treatment period with doxepin, discontinuation of doxepin for two weeks (which embraces the limitation of “at least two days” required by claims 21, 25 and 30) did not cause rebound insomnia.
12. Regarding the limitation of “providing information to the patient that between about 1 mg and about 6 mg of doxepin is effective to treat the sleep maintenance insomnia and does not cause rebound insomnia resulting from the treatment even upon abrupt discontinuation…” (claim 21), and “providing information to the patient indicating that rebound insomnia is not a side effect with the use of about 1 mg and about 6 mg of doxepin for the treatment of sleep maintenance insomnia even upon abrupt discontinuation…” (claim 30), said claims are drawn to methods wherein "an instruction limitation" (i.e., a limitation "informing" someone about the existence of an inherent property of that method) is added to a method known in the art. See King Pharmaceuticals, Inc. v. Eon Labs, Inc., 616 F.3d 1267, 1279, 95 USPQ2d 1833, 1842 (2010). Similar to the inquiry for products with printed matter thereon, for such method claims cases the relevant inquiry is whether a new and unobvious functional relationship with the known method exists. In King Pharma, the court found that the relevant determination is whether the "instruction limitation" has a "new and unobvious functional relationship" with the known method of administering the drug with food. Id.. The court held that the relationship was non-functional because "[i]nforming a patient about the benefits of a drug in no way transforms the process of taking the drug with food." Id. That is, the actual method of taking a drug with food is the same regardless of whether the patient is informed of the benefits. Id. "In other words, the ‘informing’ limitation ‘in no way depends on the method, and the method does not depend on the ‘informing’ limitation.’" Id. (citing In re Ngai, 367 F.3d 1336, 1339 (Fed. Cir. 2004)); see also In re Kao, 639 F.3d 1057, 1072-73, 98 USPQ2d 1799, 1811-12 (Fed. Cir. 2011). See MPEP 2111.05.
13. In the present case, informing the patient about the benefits of taking doxepin does not transform the process of taking doxepin for the treatment of sleep maintenance insomnia. Thus, the combined teachings of Gillin et al. and Kavey et al. suggest the same method of administering the same drug, doxepin, in a similar low dosage range, to the same patient population, a patient with sleep maintenance insomnia having a history of rebound insomnia while taking non-doxepin sleep medication, with the knowledge that doxepin has little to no incidence of adverse effects (e.g., rebound insomnia), such that the limitation of “providing information…” is not given any patentable weight.
14. In the alternative, even assuming arguendo that the limitation of “providing information to the patient…” does carry patentable weight, “[t]he doctrine of informed consent requires that a patient be given all pertinent information which will enable him to make the decision to undergo or forego a specified medical treatment. The consent cannot be legally effective unless the patient's decision is intelligently made, based on adequate information about treatment, collateral risks, and available alternatives,” (Svitak and Morin, 1986, page 543). As such, a physician treating a patient for any medical ailment is required to disclose all recognized risks/ possible side effects/ complications etc and anticipated benefits involved in the treatment or surgical procedure that might affect a patient’s treatment decision, i.e., a physician is required to inform the insomnia patient on the necessary consideration of a potential side effect of insomnia medications, (i.e., rebound insomnia or lack thereof).
Thus, in view of the combined art of record, one of skill in the art would have been motivated to administer doxepin, in a low dosage range, to a patient with sleep maintenance insomnia having a history of rebound insomnia while taking non-doxepin sleep medication, wherein the patient is informed that doxepin has little to no incidence of adverse effects (e.g., rebound insomnia),
As such, claims 21, 23-25, 30, 32-34, 36 and 38 are prima facie obvious.
Claim 22 depends from claim 21 and limits the dosage amount of doxepin to about 1 mg. Claim 26 depends from claim 25 and limits the dosage amount of doxepin to about 1 mg. Claim 31 depends from claim 30 and limits the dosage amount of doxepin to about 1 mg.
15. Kavey et al. additionally teach a dosage range of 0.5 to about 20 mg (see column 3, lines 24-31), which fully encompasses a dosage of 1 mg, required by claims 22, 26 and 31. One of skill in the art would immediately recognize that the low therapeutic dosage amount of doxepin would result in reduced incidence of any side effects, including rebound insomnia. Accordingly, one skilled in the art would have been motivated to optimize the dosage of doxepin in order to mitigate any potential side effect of sleep medication, i.e. rebound insomnia.
As such, claims 22, 26 and 31 are prima facie obvious.
Claim 40 is drawn to claim 21, wherein the rebound insomnia is measured by wake after sleep onset (WASO). Claim 41 is drawn to claim 25, wherein the rebound insomnia is measured by wake after sleep onset (WASO).
Claim 42 is drawn to claim 30, wherein the rebound insomnia is measured by wake after sleep onset (WASO).
16. Hajak et al. additionally teach that rebound analysis is conducted using WASO as 1 of 4 sleep parameters for measuring amount of rebound (Table 4 at page 459). It is noted that Hajak et al. demonstrate that patients showed rebound in 3 or 4 sleep parameters (including WASO) at nights 29, 30 and 31, but that rebound insomnia based on a total of 3 or 4 sleep parameters is not reported for the first four weeks.
Accordingly, one skilled in the art would have been motivated to employ WASO as a sleep parameter when measuring incidence of rebound insomnia in a patient following abrupt discontinuation of doxepin for a period of at least 2 days in said patient, wherein the patient does not have rebound insomnia during the discontinuation period.
As such, claims 40-42 are prima facie obvious.
17. Claims 35, 37 and 39 remain rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Gillin et al, (“Rebound Insomnia: A Critical Review,” 1989) in view of Kavey et al., (U.S. Pat. No. 5,643,897 A1), and in view of Hajak et al., (J Clin Psychiatry 2001), as applied to claims 21-34, 36 and 38, above, and further in view of W.H.O. 34th Expert Committee on Drug Dependence (ECDD), “Critical Review of Zopliclone,” April 2006.
Claims 21, 25 and 30 are addressed in detail, above.
Claim 35 depends from claim 21 and limits the non-doxepin sleep medication to a non-benzodiazepine. Claim 37 depends from claim 25 and limits the non-doxepin sleep medication to a non-benzodiazepine. Claim 39 depends from claim 30 and limits the non-doxepin sleep medication to a non-benzodiazepine.
18. Gillin et al. in view of Kavey et al. and Hajak et al. motivate one of skill in the art to treat sleep maintenance insomnia in a patient in need thereof, wherein said patient is at risk of rebound insomnia based on a history of rebound insomnia while taking one or more non-doxepin sleep medications, by administering a low therapeutic dose of doxepin (based on evidenced that doxepin results in no incidence or very low incidence of rebound insomnia), followed by discontinuing doxepin for at least two days wherein the patient does not have rebound insomnia during the discontinuation period. The combined teachings of the prior art do not teach wherein the non-doxepin sleep medication is non-benzodiazepine.
19. Yet, W.H.O. teaches that “[s]ince the beginning of its therapeutic use, zopliclone has been found to cause rebound insomnia and anxiety,” (page 10, under “6.Dependence Potential,” first sentence of second paragraph). Zopliclone is a non-benzodiazepine sleep medication.
20. Thus, it would have obvious to one skilled in the art to treat sleep maintenance insomnia in a patient in need thereof, wherein said patient is at risk of rebound insomnia based on a history of rebound insomnia while taking one or more non-doxepin sleep medications (specifically zopliclone), by administering a low therapeutic dose of doxepin, based on evidenced that doxepin results in no incidence or very low incidence of rebound insomnia, with a reasonable expectation of success.
As such, claims 35, 37 and 39 are prima facie obvious.
Response to Arguments
21. Applicant traverses the previous obviousness rejection of claims 21-34, 36 and 38 over Gillin et al., in view of Kavey et al., and in view of Hajak et al., and the rejection of claims 35, 37 and 39 over Gillin et al, in view of Kavey et al., and in view of Hajak et al., further in view of W.H.O.
Applicant argues that Hajak not only teaches that discontinuation of doxepin did cause rebound insomnia in many patients, but Hajak explicitly teaches away from the abrupt discontinuation of tricyclic antidepressants such as doxepin. Applicant argues that Hajak defines four phenomena for rebound insomnia: (i) sleep efficiency, (ii) total sleep time, (iii) wake after sleep onset, and (iv) sleep stage II percentages. Hajak also describes acute withdrawal as the first three days after cessation of doxepin. The wake after sleep onset (WASO) rebound insomnia parameter significantly increased compared to the placebo group when doxepin was discontinued; Hajak states, "[g]roup comparisons done for each night of withdrawal revealed that the amount of rebound was more expressed for WASO after acute doxepin withdrawal (night 29) (p <.05)." (See Hajak at page 459).
Applicant contends that Hajak states, "[f]ollowing doxepin treatment, the rebound rate of patients showing rebound in 3 or 4 sleep parameters was increased at all nights of acute withdrawal (nights 29, 30, and 31) compared with continuous placebo application." (See Hajak at page 459). Hajak then shows a table enumerating how many of the four rebound insomnia phenomena were still present in patients after acute withdrawal and even after two weeks' worth of withdrawal. (See Hajak Table 4 at page 459): Night 29 had 12 patients experiencing 3 and 4 rebound phenomena, nights 30 and 31 had 10 patients experiencing 3 and 4 rebound phenomena, and night 42 had 5 patients still experiencing 3 and 4 rebound phenomena. Applicant alleges that “[i]n other words, immediately after doxepin cessation (and even two weeks after), many patients experienced rebound insomnia.” (Applicant’s Remarks, page 1). Applicant argues that this is contrary to instant claims 1, 25 and 30 that recite "discontinuing the administration of doxepin for a discontinuation period of at least two days, wherein the patient does not have rebound insomnia during the discontinuation period." In Hajak, patients were still experiencing rebound insomnia acutely (i.e., 1-3 days after discontinuation) and non-acutely (i.e., 14 days after discontinuation).
22. Applicant's arguments have been fully considered but they are not persuasive. Hajak teach that when administering either doxepin or placebo to groups of insomniac patients for a period of 28 nights, followed by an abrupt discontinuation period of 2 weeks, rebound insomnia was not observed: “[d]oxepin did not cause rebound insomnia when rebound in polysomnographic sleep parameters was analyzed according to standard methods,” (page 454, right column, Figure 1 and page 461, left column, last paragraph). Hajak is relied upon for teaching the same patient population, i.e., a patient at risk of rebound insomnia who has been administered a low therapeutic dose of doxepin (based on evidenced that doxepin results in no incidence or very low incidence of rebound insomnia), followed by discontinuing doxepin for at least two days wherein the patient does not have rebound insomnia during the discontinuation period. It is noted that while Hajak discloses some patients experiencing 3 and 4 sleep parameters of rebound phenomena, said parameters are not reported until nights 29, 30 and 31, i.e., rebound insomnia based on a total of 3 and 4 sleep parameters is not reported for the first four weeks.
23. Regarding Applicant’s argument that Hajak explicitly teaches away from the abrupt discontinuation of tricyclic antidepressants such as doxepin, Hajak also teaches that “[d]oxepin did not cause rebound insomnia when polysomnographic sleep parameters was analyzed according to standard methods.” (page 461, left column, last paragraph). Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). "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." In re Gurley, 27 F.3d 551, 554, 31 USPQ2d 1130, 1132 (Fed. Cir. 1994) (The invention was directed to an epoxy impregnated fiber-reinforced printed circuit material. The applied prior art reference taught a printed circuit material similar to that of the claims but impregnated with polyester-imide resin instead of epoxy. The reference, however, disclosed that epoxy was known for this use, but that epoxy impregnated circuit boards have "relatively acceptable dimensional stability" and "some degree of flexibility," but are inferior to circuit boards impregnated with polyester-imide resins. The court upheld the rejection concluding that applicant’s argument that the reference teaches away from using epoxy was insufficient to overcome the rejection since "Gurley asserted no discovery beyond what was known in the art." 27 F.3d at 554, 31 USPQ2d at 1132). Furthermore, "[t]he prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed…." In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004).
And, a reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill the art, including nonpreferred embodiments. Merck & Co. v. Biocraft Laboratories, 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989). See also Upsher-Smith Labs. v. Pamlab, LLC, 412 F.3d 1319, 1323, 75 USPQ2d 1213, 1215 (Fed. Cir. 2005)(reference disclosing optional inclusion of a particular component teaches compositions that both do and do not contain that component); Celeritas Technologies Ltd. v. Rockwell International Corp., 150 F.3d 1354, 1361, 47 USPQ2d 1516, 1522-23 (Fed. Cir. 1998) (The court held that the prior art anticipated the claims even though it taught away from the claimed invention. "The fact that a modem with a single carrier data signal is shown to be less than optimal does not vitiate the fact that it is disclosed.").
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As such, at the time of filing, one skilled in the art one would reasonably expect that even upon abrupt discontinuation of doxepin, rebound insomnia would not occur. It is noted that the limitation of the duration of treatment has not been incorporated into the instant claims.
24. It is noted that in the study at pages 31-33 of the Specification, Applicant alleges unexpectedly beneficial results upon the abrupt discontinuation of doxepin: “discontinuation of doxepin does not cause rebound insomnia after 35 days of treatment,” (Specification, at [0116]). However, the results of this study are limited to a 2-day discontinuation period (paragraph [0116]). Applicant has not established that when administered at a dosage amount of 3 mg or 6 mg, doxepin is effective in the treatment of sleep maintenance insomnia with no incidence of rebound insomnia upon abrupt discontinuation, beyond a 2-day discontinuation period. Thus, absent evidence that doxepin is effective in the treatment of sleep maintenance insomnia even upon abrupt discontinuation with no incidence of rebound insomnia beyond a period of two days, the rejection is maintained.
Conclusion
25. Claims 21-42 are currently pending in the application, and all claims are rejected. No claim is presently allowable.
26. 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.
27. Any inquiry concerning this communication or earlier communications from the examiner should be directed to JANET L COPPINS whose telephone number is (571)272-0680. The examiner can normally be reached on Monday-Friday 8:30AM-5PM EST.
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/JANET L COPPINS/Examiner, Art Unit 1628
/JARED BARSKY/Primary Examiner, Art Unit 1628