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 .
Continued Examination Under 37 CFR 1.114
2. A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on September 18, 2026 has been reviewed by the examiner and entered of record in the file.
3. Claims 1, 19 and 20 are amended.
4. Claims 5 and 11-18 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, without traverse, there being no allowable generic or linking claim.
5. Applicant previously elected the species of (a) naltrexone, (b) calcitriol, and (d) simultaneous administration. The non-elected species remain withdrawn from further consideration as drawn to nonelected subject matter.
6. Claims 1-4, 9, 19, and 20 are under examination with the elected species and are the subject of this office action.
Priority
7. Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 365(c) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
8. The disclosure of the prior-filed foreign application, Application No. GB 1805207.6, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application, as follows:
Applicant’s claims, as amended, require the limitation of the daily dose of Vitamin D product, i.e., “wherein the vitamin D product is administered at a daily dose in the range of about 2,000 IU to 8,000 IU per dosage form.” However, in foreign priority document GB 1805207.6, the only mention of dose amount of the vitamin D product is:
“[i]n another embodiment, the vitamin D or analogue thereof of pharmaceutically acceptable salt of either is administered at a dose in the range of about 400 IU to about 10,000 IU per dosage form,” (page 7, lines 23-25 and see page 9, lines 1-2).
Thus foreign application GB 1805207.6 fails to provide support for the daily dose amount or daily dose range of the Vitamin D product, and the instant claims are afforded benefit of priority to U.S. Application 17/042,904, filed September 28, 2020.
Previous Claim Rejections - 35 USC § 112
9. Claims 1-4, 9, 19 and 20 were previously 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.
10. Claim 1 was previously rejected as being indefinite for reciting the limitation of the dose amount of Vitamin D product: “wherein the vitamin D product is administered at a daily dose in the range of about 2,000 IU to 8,000 IU per dosage form.”
In view of Applicant’s amendment to delete the recitation of “per dosage form” and add the limitation of “single daily dose” the previous indefiniteness rejection is withdrawn.
11. Claim 19 was previously rejected as being indefinite for reciting limitation of the dose amount of Vitamin D product: “wherein the vitamin D product is administered at a daily dose in the range of about 3,000 IU to 7,000 IU per dosage form,”
In view of Applicant’s amendment to delete the recitation of “per dosage form” and add the limitation of “single daily dose” the previous indefiniteness rejection is withdrawn.
12. Claim 20 was previously rejected as being indefinite for reciting the limitation of the dose amount of Vitamin D product: “wherein the vitamin D product is administered at a daily dose of about 5,000 IU per dosage form.”
In view of Applicant’s amendment to delete the recitation of “per dosage form” and add the limitation of “single daily dose” the previous indefiniteness rejection is withdrawn.
Previous Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
13. Claims 1-4, 9, 19 and 20 were previously rejected under 35 U.S.C. 103 as being unpatentable over Sherman and Atkinson, U.S. Pat. No. 4,857,533 A, in view of Lima et al., (Arthritis Care and Research 2016), as evidenced by Patel et al., (Practical Gastroenterology 2021). In view of Applicant’s amendment to the claims to require a single daily dose, the previous rejection has been modified as follows below.
14. Claims 1-4, 9, 19 and 20 remain rejected under 35 U.S.C. 103 as being unpatentable over Sherman and Atkinson, U.S. Pat. No. 4,857,533 A, in view of Lima et al., (Arthritis Care and Research 2016), as evidenced by Patel et al., (Practical Gastroenterology 2021), and further in view of McCullough et al., Journal of Steroid Biochemistry and Molecular Biology (2019).
This rejection has been modified as a result of Applicant’s amendment to the claims.
Claim 1, as amended, is drawn to a method of treating an autoimmune disease (more specifically, Systemic Lupus Erythematosus (SLE)), comprising administering separately, sequentially or simultaneously (more specifically, simultaneously (claim 3)) to a subject in need thereof,
(i) a naltrexone product or an analogue thereof, (more specifically, naltrexone (claim 9)), at a dose of from 1 to 5 mg, and
(ii) the vitamin D product calcitriol, administered as a single daily dose in the range of about 2,000 IU to 8,000 IU.
Claim 19 is drawn to claim 1 and limits wherein the vitamin D product is administered as a single daily dose in the range of about 3,000 IU to 7,000 IU (more specifically a single daily dose of about 5,000 IU (claim 20)).
Claim 4 is drawn to claim 1, and limits wherein the naltrexone product and the vitamin D product are administered as a combined preparation.
15. Sherman teaches a method of treating systemic lupus erythematosus in a patient in need thereof, comprising administering nalmefene orally in 1.0 mg tablets twice daily, (see Example, column 5). Sherman additionally recites a method of treating systemic lupus erythematosus in a patient in need thereof comprising administering nalmefene or naltrexone in an oral dosage form comprising a tablet, capsule, caplet or liquid containing from about 0.5 to about 50.0 mg nalmefene or naltrexone, which meets the limitation of from 1 to 5 mg required by instant Claim 1 (see Sherman claims 1-5). Considering that the genus of narcotic antagonists disclosed by Sherman comprises only two compounds, i.e., nalmefene and naltrexone, one skilled in the art before the effective filing date of the claimed invention would have immediately envisaged selecting naltrexone for the treatment of systemic lupus erythematosus in a patient in need thereof, and would have a reasonable expectation of success.
16. Sherman is silent to the administration of calcitriol.
17. Yet, Lima et al. teaches that vitamin D supplementation in patients with systemic lupus erythematosus (SLE) resulted in decreased disease activity and improved fatigue in SLE patients (See abstract). Lima et al. teach the administration of vitamin D in the form of oral cholecalciferol tablets at a dose of 50,000 IU/week (page 92, right column, under “Randomization and blinding”), equivalent to a dose of 7,142.86 IU/day, which is within the range of about 2,000 IU to 8,000 IU daily dose required by claim 1 and about 3,000 IU to about 7,000 IU daily dose required by claim 19. And, McCullough et al. specifically disclose the administration of Vitamin D3 in a dose amount of 5,000 IU once daily for 12 months or longer (page 231, left column, first paragraph under “Results”). Therefore one skilled in the art would have been motivated to administer Vitamin D3 in an amount of 5,000 IU in a single daily dose, with a reasonable expectation of success. And, it would have been obvious to one of skill in the art before the effective filing date of the claimed invention to use the starting dose of about 5000 IU/day in a single dose and optimize said dose in order to achieve a beneficial effect in a method of treating SLE.
Moreover, the determination of known effective amounts of known active agents to be administered to treat the same disease is considered well in the competence level of an ordinary skilled artisan in pharmaceutical science, involving merely routine skill in the art. And, discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art. See In re Boesch, 617 F.2d 272, 205 USPQ 215 (CCPA 1980), thus resulting in the practice of claim 20, with a reasonable expectation of success.
18. As evidenced by Patel et al., both cholecalciferol and calcitriol are formulations in the Vitamin D family: cholecalciferol is Vitamin D3, while calcitriol is the active form of cholecalciferol (page 22, Table 1). Considering that the genus of Vitamin D analogs in Table 1 comprises only four compounds, i.e., ergocalciferol, cholecalciferol, calcidiol, and calcitriol, one skilled in the art would have immediately envisaged substituting the active metabolite calcitriol for cholecalciferol in the treatment of systemic lupus erythematosus in a patient in need thereof.
19. As such, one skilled in the art before the effective filing date of the claimed invention would have been motivated to administer calcitriol at a dose of about 7,000 IU/day to a patient suffering from SLE, with a reasonable expectation of success.
20. Thus, nothing unobvious is seen in combining the teachings of Sherman and Lima et al. in a method of simultaneously administering a combination of naltrexone and calcitriol to treat SLE in a patient in need thereof. The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law, please see In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). See also In re Kotzab, 217 F.3d 1365, 1370, 55 USPQ2d 1313, 1317 (Fed. Cir. 2000) (setting forth test for implicit teachings); In re Eli Lilly & Co., 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (discussion of reliance on legal precedent); In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings). Furthermore, MPEP 2144 teaches that the strongest rationale for combining references is a recognition, expressly or impliedly in the prior art or drawn from a convincing line of reasoning based on established scientific principles or legal precedent, that some advantage or expected beneficial result would have been produced by their combination.
21. In the instant case, two known compounds which individually demonstrate activity against SLE when administered orally in the form of tablets could be combined for simultaneous administration (or in a combined preparation as recited in claim 4) in order to achieve an additive effect, with the expected result of an effective treatment for the autoimmune disease SLE.
22. Please refer to MPEP 2144.06 “I. COMBINING EQUIVALENTS KNOWN FOR THE SAME PURPOSE” wherein Kerkhoven is specifically referenced:
“It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted) (Claims to a process of preparing a spray-dried detergent by mixing together two conventional spray-dried detergents were held to be prima facie obvious.). See also In re Crockett, 279 F.2d 274, 126 USPQ 186 (CCPA 1960) (Claims directed to a method and material for treating cast iron using a mixture comprising calcium carbide and magnesium oxide were held unpatentable over prior art disclosures that the aforementioned components individually promote the formation of a nodular structure in cast iron.); and Ex parte Quadranti, 25 USPQ2d 1071 (Bd. Pat. App. & Inter. 1992) (mixture of two known herbicides held prima facie obvious).
23. As stated by the Court in KSR International Co., v. Teleflex Inc., 127 US 1727 (2007), “when a patent ‘simply arranges old elements with each performing the same function it had been known to perform’ and yields no more than one would expect from such an arrangement, the combination is obvious” (quoting Sakraida v. AG Pro, Inc., 425 US 273 (1976); see also: Merck v. Biocraft (874 F.2d 804, 807 (Fed. Cir. 1989), indicating that it is a matter of obviousness for one of ordinary skill in the art to select a particular component from among many disclosed by the prior art as long as it is taught that the selection will result in the disclosed effect, even when the possible selections number 1200 or in the thousands; Sundance, Inc. v. DeMonte Fabricated, Ltd., 550 F.3d 1356 (Fed. Cir. 2008): a claimed invention is obvious is it is a combination of known prior art elements that would reasonably have been expected to maintain their respective properties or functions after they had been combined.
As such, claims 1, 3, 4, and 19 are prima facie obvious.
Claim 2 is drawn to claim 1, and limits wherein the vitamin D product is administered to the subject in an amount sufficient to bring the subject's blood vitamin D concentration to within a range of from 40 to 120 ng/ml.
24. Claim 2 depends from claim 1 and is drafted in terms of the intended outcome of the administration of the Vitamin D: “...wherein the vitamin D product is to be administered to the subject in an amount sufficient to bring the subject's blood vitamin D concentration to within a range of from 40 to 120 ng/ml.” However, a claimed composition maybe obvious because it was suggested by, or structurally similar to, a prior art composition even though a particular benefit of the claimed composition asserted by patentee is not expressly disclosed in the prior art. It is the differences in fact in their respective properties which are determinative of nonobviousness. If the prior art composition does in fact possess a particular benefit, even though the benefit is not recognized in the prior art, Applicant's recognition of the benefit is not in itself sufficient to distinguish the claimed composition from the prior art, In re Dillon, 919 F.2d 688, 16 USPQ2d 1897 (Fed. Cir. 1991). In this case, the increase in blood vitamin D concentration is considered a latent property of the administration of calcitriol, as previously disclosed by Lima et al., and the alleged unexpected result does not confer patentability.
As such, claim 2 is prima facie obvious.
Response to Arguments
25. Applicant traverses the obviousness rejection over Sherman in view of Lima and as evidenced by Patel.
Applicant argues that Lima et al. is directed to a clinical study using oral cholecalciferol, not calcitriol, wherein juvenile-onset SLE patients received cholecalciferol at 50,000 IU/week for 24 weeks, and the study assessed the effect of that supplementation on serum 25-hydroxyvitamin D levels, disease activity and fatigue. Applicant contends that Lima does not disclose administering calcitriol, do not test calcitriol, and do not suggest replacing cholecalciferol with calcitriol.
Applicant contends with the office’s position that Patel provides evidence that calcitriol was one of a number of known vitamin D-related products and would thus be immediately obvious to the skilled person. Applicant alleges that Patel contradicts this assumption because Patel states that cholecalciferol is generally the preferred formulation for vitamin D supplementation, such that a skilled person would have had a reason to use cholecalciferol, because that is what Lima et al. used, and Patel et al. confirm that cholecalciferol was the usual supplementation product.
A teaching that calcitriol exists as a vitamin D product in a document
published after the priority date of the claimed invention, especially where that document then teaches away from the use of calcitriol, should not be considered to establish a case of prima facie obviousness against the present claims.
Applicant argues the office’s position that two known compounds individually active against SLE could be combined to achieve an additive effect. Applicant alleges that Lima shows cholecalciferol supplementation in juvenile-onset SLE patients and Patel provides evidence that calcitriol exists.
Applicant argues that Lima’s teaching of the administration of vitamin D in the form of oral cholecalciferol tablets at a dose of 50,000 IU/week does not provide a calcitriol dosing regimen for SLE from which the claimed dose could be obtained by routine optimization.
26. Applicant's arguments have been fully considered but they are not persuasive. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In this case, the primary reference, Sherman, discloses a method of treating systemic lupus erythematosus in a patient in need thereof, comprising administering nalmefene orally in 1.0 mg tablets twice daily, (see Example, column 5), and suggests naltrexone in an oral dosage form in an amount of about 0.5 to about 50.0 mg, which meets the limitation of from 1 to 5 mg required by claim 1. Lima is relied upon for suggesting that vitamin D supplementation in patients systemic lupus erythematosus (SLE) mitigated symptoms of SLE, and teach the administration of vitamin D in the form of oral cholecalciferol tablets at a dose of 50,000 IU/week which is equivalent to a dose of 7,142.86 IU/day, and wherein McCullough teaches the administration of 5000 IU of vitamin D3 once daily for 12 months or longer. Patel is relied upon for evidencing that both cholecalciferol and calcitriol are formulations in the Vitamin D family. And, regarding the teaching of Patel, 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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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).
Regarding Applicant’s previous allegation of synergism, even if it was agreed upon that the claimed method provided synergistic results, more would be required to show nonobviousness, as synergism is not per se unexpected. See In re Diamond, 360 F. 2d 214, 218 ( CCPA 1966). (“What section 103 requires is ‘unexpected synergism’ ... “ (pg. 216, n.7); “we attribute no magic status to synergism per se since it may be expected or unexpected"” (pg. 218)(emphasis added)). In the instant case, the combination of familiar elements naltrexone and calcitriol, each previously disclosed for the treatment or supplemental treatment of SLE in the same dose amounts, according to known methods, is likely to be obvious when it does no more than yield predictable results, i.e., successful treatment of SLE in a patient in need thereof.
And regarding the allegation of synergistic/ unexpected results demonstrated in the specification, synergism requires a combination of specific ingredients in specific amounts. The instant claims are not drafted commensurate in scope with the unexpected results demonstrated in the Specification, that is, the claims presently embrace a broader scope of ingredients and amounts than the synergistic amounts demonstrated in Example 3. The results demonstrated in Example 3 were achieved by administering calcitriol at a dose of 5,000 IU and administering the single naltrexone product, naltrexone, at a dose of 4.5 mg.
27. Thus, Sherman in view of Lima et al. as evidenced by Patel and in view of McCullough suggest the combined administration of naltrexone and calcitriol in the form of oral tablets at dosage amounts that are within the dose ranges recited by the instant claims, for the treatment of SLE in a patient in need thereof.
Absent a demonstration of unexpected results that are commensurate in scope with the present claims, one skilled in the art before the effective filing date of the claimed invention would have been motivated to combine the teachings of the prior art for an improved treatment of SLE in a patient in need thereof, with a reasonable expectation of success.
Conclusion
28. In conclusion, claims 1-5, 9 and 11-20 are present in the application. Claims 5 and 11-18 are withdrawn from consideration. Claims 1-4, 9, 19 and 20 are rejected. No claim is currently allowable.
29. 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 Monday-Friday 8:30AM-5PM EST.
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/JANET L COPPINS/Examiner, Art Unit 1628
/AMY L CLARK/Supervisory Patent Examiner, Art Unit 1628
