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 .
Response to Amendments
Applicant's amendments filed 1/27/2025 to claims 116 and 130 have been entered. Claims 148-153 have been added. Claims 116, 118-120, 126, 128-133, 136-138 and 143-153 remain pending and are being considered on their merits. References not included with this Office action can be found in a prior action. Any rejections of record not particularly addressed below are withdrawn in light of the claim amendments and applicant’s comments.
Election/Restrictions
Applicant’s election without traverse of Group I (claims 116-133 and 136-137), and the species of “alleviating” (claims 116 and 130) and “miltefosine” (claims 121, 123, 125, and 127), in the reply filed on 12/4/2017 stands. In view of the applicant’s amendments the requirement for the election of a species of disorder has been withdrawn.
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.
Claims 116, 128, 136-138 and 143-153 are rejected under 35 U.S.C. 103 as being unpatentable over Verhaar et al (2013, Inflamm. Bowel Dis., 19(9): 1974-1982) in view of Palombella et al (U.S. PGPUB 20130344061), Weller et al (2009, J Invest Dermatol., 129(2):496-8; reference U) and Sundar et al (2003, Pediatr Infect Dis J., 22: 434–8; reference V).
Verhaar is drawn to the use of immunomodulators for the treatment of inflammatory bowel disease, and specifically the immunomodulator miltefosine (see abstract Regarding claims 116 and 128, Verhaar is drawn to a method of suppressing inflammation associated with inflammatory bowel disease by treatment with miltefosine (see title and abstract). Regarding claims 116, 136, 138 and 142, Verhaar teaches administering miltefosine twice weekly to mice with symptoms of inflammatory bowel disease, and Verhaar teaches this treatment alleviating their symptoms (see abstract and page 1975). Regarding claims 136-137, Verhaar teaches miltefosine is a useful treatment not only in mice, but that it is also used in humans, and that it has a half-life of 7 days (see page 1974). Regarding claims 116 and 137, Verhaar teaches that miltefosine works to inhibit T-cell activation and proliferation and that it is used to treat a variety of inflammatory conditions in humans (see pages 1974-1975). Verhaar teaches the miltefosine treatment significantly reduced proinflammatory cytokines IL-6, TNF-alpha and interferon (see col. 1 on page 1981).
Verhaar does not teach exemplify treating one of the conditions in claim 116 or treating humans (claim 137). Verhaar is silent as to if the amount of miltefosine is sufficient to activate NKT-2 cells and CD8αα+ T cells in the liver (116 and 128). Verhaar does not teach that the twice weekly dose is 0.1 to 4 mg/kg, 0.2 to 0.5 mg/kg, 0.2 to 1 mg/kg, 0.5 to 3 mg/kg, 0.5 to 1 mg/kg, 1 to 3 mg/kg, or 2 to 3 mg/kg per day (claims 116 and 148-153).
Like Verhaar, Palombella is drawn to treating various inflammatory conditions by administering an immunomodulator compound to reduce inflammation in mammals and humans (see abstract and paragraphs [0011] and [0042]). Regarding claims 116, 143, and 144-147, Palombella teaches such inflammatory conditions include hepatitis, nonalcoholic steatohepatitis, alcohol induced liver fibrosis, lupus erythematosus, and different types of the genius of sclerosis (see paragraphs [0027], [0028], [0038], [0458] and [0471]). Palombella teaches inflammatory bowel disease is a fibrosis associated with a hindgut inflammatory disorder (see paragraph [0473]). Palombella teaches that such conditions can be treated by an agent that prevents mast cell degranulation and by inhibiting proinflammatory cytokines including IL-6, TNF-alpha and interferon (paragraphs [0052], [0166], [0435] and [0498]).
Regarding claims 116 and 148-153, Weller teaches that miltefosine dose dependently 5 - 25 µM (2 - 10 µg/mL), inhibited inhibition of TNF release and mast cell degranulation in vitro, with a maximal effect at 25 µM (10 µg/mL) (see page 496, col. 3 on page 497, col. 1 on page 498, and Figure 1). Regarding claims 116 and 148-153, Weller teaches these effects of miltefosine appears not to be limited to IgE-dependent activation nor to histamine release but also comprises alternative IgE-independent activation pathways and release of cytokines (see col. 1 on page 498). Regarding claims 116 and 148-153, Weller teaches that these results provide proof-of-concept that miltefosine also inhibits inflammatory responses in vivo and indicates that agents such as miltefosine, have the potential as new therapeutics for the treatment of mast cell driven diseases (see col. 1 page 497).
Regarding claims 116 and 148-153, Sundar teaches results of a Phase I/II dose ranging study of miltefosine treatment, wherein subjects were given doses 1.5 mg/kg/day (Group A) and 2.5 mg/kg/day (Group B) (see abstract). Regarding claims 116 and 148-153, Sundar teaches the mean plasma concentration of miltefosine in the treated subjects was 15.8 µg/mL (range of 7 to 31 µg/mL) for 1.5 mg/kg/day dose Group A and 26 µg/mL (range of 4.1 to 69 µg/mL) for 2.5 mg/kg/day dose Group B (see page 437). Regarding claims 116 and 148-153, Sundar teaches that while generally both dose of 1.5 mg/kg/day (Group A) and 2.5 mg/kg/day (Group B) were well tolerated, as per the adult experience, gastrointestinal adverse events were seen: 33 and 39% of children experienced vomiting and 5 and 17% experienced diarrhea in Groups A and B, respectively (see abstract and Table 3).
It would have been obvious to combine Verhaar with Palombella and Weller to treat other inflammatory conditions in humans or mammals with Palombella’s listed diseases. A person of ordinary skill in the art would have had a reasonable expectation of success in using Verhaar’s method to treat inflammatory conditions because Verhaar teaches that miltefosine is used to treat a variety of inflammatory conditions in humans and Verhaar establishes that the known role in the treatment is to reduce inflammatory responses. Additionally, Palombella teaches inflammatory bowel disease is a fibrosis associated with a hindgut inflammatory disorder, and Palombella highlights that other inflammatory conditions are also linked to fibrosis. Furthermore, Palombella teaches that such conditions can be treated by an agent that prevents mast cell degranulation and by inhibiting proinflammatory cytokines, while Weller establishes that miltefosine prevents mast cell degranulation and both Verhaar and Weller teach miltefosine inhibits proinflammatory cytokines. The skilled artisan would have been motivated to use Verhaar’s method to treat hepatitis, nonalcoholic steatohepatitis, alcohol induced liver fibrosis, lupus erythematosus, and different types of the genius of sclerosis because Palombella highlights that these are inflammatory conditions that can be treated by administering an immunomodulator, and specifically one that functions to prevent mast cell degranulation and inhibits proinflammatory cytokines, while Weller establishes that miltefosine prevents mast cell degranulation and both Verhaar and Weller teach miltefosine inhibits proinflammatory cytokines. Additionally, Palombella teaches inflammatory bowel disease, which is the inflammatory condition taught by Verhaar, is a fibrosis associated with a hindgut inflammatory disorder, and therefore Palombella establishes that fibrosis is associated with the inflammatory condition treated Verhaar’s method which further provides motivation to use Verhaar’s treatment to treat other fibrosis associated with the inflammatory conditions. Furthermore, Verhaar teaches the miltefosine treatment significantly reduced proinflammatory cytokines IL-6, TNF-alpha and interferon, and Palombella teaches that inhibiting these same cytokines is a useful treatment for other inflammatory conditions. Finally, Weller teaches that their findings that miltefosine prevents mast cell degranulation and inhibits TNF release provide proof-of-concept that miltefosine also inhibits inflammatory responses in vivo and indicate that agents such as miltefosine, have the potential as new therapeutics for the treatment of mast cell driven diseases while Palombella establishes that these conditions can be treated by an agent that prevents mast cell degranulation and by inhibiting proinflammatory cytokines.
It would have been obvious to further combine Verhaar in view of Palombella and Weller with Sundar to treat the subject in Verhaar’s method in view of Palombella and Weller with is 0.1 to 4 mg/kg, 0.2 to 0.5 mg/kg, 0.2 to 1 mg/kg, 0.5 to 3 mg/kg, 0.5 to 1 mg/kg, 1 to 3 mg/kg, or 2 to 3 mg/kg miltefosine per day in Verhaar’s twice weekly treatment. A person of ordinary skill in the art would have had a reasonable expectation of success in treating the subject in Verhaar’s method in view of Palombella and Weller with 0.1 to 4 mg/kg, 0.5 to 3 mg/kg, 1 to 3 mg/kg, or 2 to 3 mg/kg miltefosine per day in Verhaar’s twice weekly treatment because Verhaar establishes that miltefosine is a useful treatment in mammals and humans, and Sundar provides results of a Phase I/II dose ranging study of miltefosine treatment, wherein subjects were given doses 1.5 mg/kg/day or 2.5 mg/kg/day, and that such doses were generally well tolerated. Furthermore, Sundar establishes that such doses provide subjects with plasma concentration of miltefosine that Weller’s in vitro data show are effective for achieving the desired results of preventing mast cell degranulation and inhibiting TNF release. Additionally, a person of ordinary skill in the art would also have had a reasonable expectation of success in treating the subject in Verhaar’s method in view of Palombella and Weller with 0.2 to 0.5 mg/kg, 0.2 to 1 mg/kg, or 0.5 to 1 mg/kg miltefosine per day in Verhaar’s twice weekly treatment because Sundar’s results show that even subjects that were given doses 1.5 mg/kg/day provided subjects with plasma concentrations of miltefosine that Weller’s in vitro data show are higher than what is effective for achieving the desired results of preventing mast cell degranulation and inhibiting TNF release, therefore there is a reasonable expectation of success to reduce the dose amount. The skilled artisan would have been motivated to treat the subject in Verhaar’s method in view of Palombella and Weller with 0.1 to 4 mg/kg, 0.2 to 0.5 mg/kg, 0.2 to 1 mg/kg, 0.5 to 3 mg/kg, 0.5 to 1 mg/kg, 1 to 3 mg/kg, or 2 to 3 mg/kg miltefosine per day in Verhaar’s twice weekly treatment because Sundar provides results of a Phase I/II dose ranging study of miltefosine treatment, wherein subjects were given doses 1.5 mg/kg/day or 2.5 mg/kg/day, and that such doses were generally well tolerated, and, Sundar establishes that such doses provide subjects with plasma concentrations of miltefosine that Weller’s in vitro data show are higher than what is needed for achieving the desired results of preventing mast cell degranulation and inhibiting TNF release, therefore providing motivation to use lower doses than those exemplified in Sundar. Furthermore, Sundar teaches that adverse gastrointestinal events did occur at higher frequency when subjects were given higher doses, therefore providing further motivation to use lower doses than those exemplified in Sundar. It is further obvious to modify the dose since Sundar establishes that giving subjects identical dose results in variable plasma concentrations, thereby providing additional motivation to optimize the dose to achieve a plasma level that achieves the desired effect. Finally, it is noted that the dosing amount is result effective as the references teach that the desired effects of the treatment are dose dependent.
Verhaar is silent as to if administering miltefosine in Verhaar’s twice weekly miltefosine treatment is sufficient to inherently activate NKT-2 cells and CD8αα+ T cells in the liver. However, as stated above, Verhaar teaches that this dose of miltefosine is sufficient to alleviate the symptoms of the inflammatory condition, the references render it obvious to use a dose that is within each of the claimed ranges, and therefore it reads on the claimed “effective amount”.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill at the time the invention was made.
Claims 118-120, 126 and 130-133 are rejected under 35 U.S.C. 103 as being unpatentable over Verhaar et al (2013, Inflamm. Bowel Dis., 19(9): 1974-1982) in view of Palombella et al (U.S. PGPUB 20130344061), Weller et al (2009, J Invest Dermatol., 129(2):496-8) and Sundar et al (2003, Pediatr Infect Dis J., 22: 434–8) as applied to claims 116, 128, 136-138 and 143-153 above, and further in view of Halder et al (2007, J Clin Invest., 117(8): 2302-2312) and Saini et al (2005, Current Pharmaceutical Design, 11: 273-280).
The teachings of Verhaar in view of Palombella, Weller and Sundar are discussed and relied upon above and are apply to the teachings of claims 130-132.
Verhaar does not teach administering an RAR agonist (claims 118-120 and 133) that is tazarotene (claim 126). Verhaar does not teach administering a sulfatide to activate NKT-2 cells (claim 130 and 132).
Regarding claims 118-120, 126, 131 and 133, Halder is drawn to methods to treat a of variety of inflammatory diseases, and that the treatment the mechanism of treating inflammation includes treatment results in inactivation of type 1 NKT cells (see abstract and page 2302). Regarding claims 130-132, Halder teaches administering sulfatide, an activator of NKT-2 cells, in an amount sufficient to activate said cells, to treat a mouse model of inflammatory liver disease (see abstract and page 2311). Regarding claims 130-132, Halder teaches activating NKT-2 cells using compounds such as sulfatides, is a new approach that could be used to teach a variety of inflammatory diseases (see abstract and page 2302). Halder teaches they also preformed this same method of administering sulfatide to activate NKT-2 cells to treat mouse models of multiple sclerosis (see col. 1 on page 2311), and Halder states their method could lead to treatments for various inflammatory diseases, including autoimmunity (see abstract). Halder teaches that their mouse model mimics inflammatory liver conditions in humans, and Halder contemplates their therapy as being useful for clinical applications (see col. 1 on page 2302 and col. 1 on page 2311).
Regarding claims 118-120, 126 and 133, Saini teaches tazarotene is an anti-inflammatory drug that is administered orally, is a RAR agonist, and that it’s mechanism of action is to regulate immune cell activity (see Table 1 and page 278).
It would have been obvious to combine Verhaar in view of Palombella, Weller and Sundar with Halder and Saini to administer Saini’s tazarotene along with Verhaar’s anti-inflammation treatment. A person of ordinary skill in the art would have had a reasonable expectation of success in administering Saini’s tazarotene along with Verhaar’s anti-inflammation treatment because Verhaar and Halder establish that both are taught to be useful treatments in the same pathological situations. The skilled artisan would have been motivated to include Saini’s tazarotene along with Verhaar’s anti-inflammation treatment because Halder establishes that inactivation of type 1 NKT cells is useful for treating inflammation.
It would have been obvious to combine Verhaar in view of Palombella, Weller and Sundar with Halder and Saini to administer Saini’s tazarotene in an amount sufficient to inactivate of type 1 NKT cells. A person of ordinary skill in the art would have had a reasonable expectation of success in administering Saini’s tazarotene in an amount sufficient to inactivate of type 1 NKT cells because Saini teaches tazarotene is an anti-inflammatory drug that’s mechanism of action is to regulate immune cell activity. The skilled artisan would have been motivated to include Saini’s tazarotene in an amount sufficient to inactivate of type 1 NKT cells because Halder teaches that the mechanism of treating inflammation in their method was that the treatment results in inactivation of type 1 NKT cells.
It would have been obvious to combine Verhaar in view of Palombella, Weller and Sundar with Halder to administer Halder’s sulfatide in an amount to activate NKT-2 cells in Verhaar’s method to treat other inflammatory conditions including Palombella’s listed diseases. A person of ordinary skill in the art would have had a reasonable expectation of success in including Halder’s sulfatide in an amount to activate NKT-2 cells in Verhaar’s method in view of Palombella because Halder teaches sulfatides can activate NKT-2 cells, and Halder teaches that the sulfatide treatment can be useful for a variety of inflammatory conditions. The skilled artisan would have been motivated to include Halder’s sulfatide in an amount to activate NKT-2 cells in Verhaar’s method in view of Palombella because Halder teaches that the sulfatide treatment can be useful for a variety of inflammatory conditions and Verhaar’s method in view of Palombella is directed towards treating inflammatory conditions.
A person of ordinary skill in the art would have had a reasonable expectation of success in administering the treatments either together or separately because both are taught to be useful for the same purpose, treating inflammation. The skilled artisan would have been motivated administer the treatments either together or separately because this would allow for the method to be adapted to the patient’s needs and to the drugs availability.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill at the time the invention was made.
Claims 129 is rejected under 35 U.S.C. 103 as being unpatentable over Verhaar et al (2013, Inflamm. Bowel Dis., 19(9): 1974-1982) in view of Palombella et al (U.S. PGPUB 20130344061), Weller et al (2009, J Invest Dermatol., 129(2):496-8) and Sundar et al (2003, Pediatr Infect Dis J., 22: 434–8), as applied to claims 116, 128, 136-138 and 143-153 above, and further in view of Chaturvedi (2007, U.S. PGPUB 2007/0286849).
The teachings of Verhaar in view of Palombella, Weller and Sundar are discussed and relied upon above.
Verhaar does not teach the method further comprises administering CD8αα+, TCRαβ+ T cells (claim 129).
Chaturvedi is drawn to methods for the treatment of immune related diseases or disorders characterized by inflammation (see abstract and paragraph [0008]). Regarding claim 129, Chaturvedi teaches activation of CD8αα+ T cells protects from progression of immune disease (see Example 7). Regarding claim 129, Chaturvedi teaches administering CD8αα+, TCRαβ+ T cells is an preferred means of treatment for autoimmune or immune related diseases or disorders (see paragraphs [0050]-[0054]).
It would have been obvious to combine Verhaar in view of Palombella, Weller and Sundar with Chaturvedi to administer Chaturvedi’s CD8αα+, TCRαβ+ T cells along with Verhaar’s anti-inflammation treatment. A person of ordinary skill in the art would have had a reasonable expectation of success in administering Chaturvedi’s CD8αα+, TCRαβ+ T cells along with Verhaar’s anti-inflammation treatment because both are taught to be useful treatments in the same pathological situations. The skilled artisan would have been motivated to include Chaturvedi’s CD8αα+, TCRαβ+ T cells along with Verhaar’s anti-inflammation treatment because both are taught to be useful for treating inflammation.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill at the time the invention was made.
Response to Arguments
Applicant's arguments filed 1/27/2025 have been fully considered but they are not persuasive. The response to arguments made 6/3/2025 are incorporated herein.
Applicant argues that the rejection is impermissible hindsight and pieces several references to meet the limitations without any motivation or reason for success. Applicant argues that Palombella that does not teach immunomodulator compounds in general but teach PI2 kinase inhibitor along with other compounds. Applicant argues the substitution of one immunodulator with another immunomodulator (e.g., a PI3K inhibitor) for another (e.g., miltefosine) will not predictably be an effective treatment for each and every inflammatory condition.
The instant rejection is based on the mechanism of miltefosine and why one of ordinary skill would expect and extend treatment of IBD to the instantly claimed diseases.
Verhaar teaches that miltefosine works to inhibit T-cell activation and proliferation and that it is used to treat a variety of inflammatory conditions in humans (see pages 1974-1975). Verhaar teaches the miltefosine treatment significantly reduced proinflammatory cytokines IL-6, TNF-alpha and interferon (see col. 1 on page 1981). Further Verhaar teaches miltefosine inhibits phospholipase C, phospholipase D, and protein kinase C.Thus, Verhaar teaches T cells depends on the activation phospholipase D, and protein kinase C and thus inhibit T cell activation. Verhaar ultimately states that treatment with miltefosine since ameliorates severity T cell dependent murine model of IBD. See page 1975. Palombella teaches “Methods, compositions, and kits for treating or preventing lupus, a fibrotic condition (e.g., fibrosis), inflammatory myopathies (e.g., myositis, e.g., dermatomyositis, polymyositis, and inclusion body myositis) and other disorders (e.g., skin conditions, e.g., skin rashes) [by] administering a PI3K inhibitor, alone or in combination with other agents or therapeutic modalities, to a subject, e.g., a mammalian subject, e.g., a human.” The reference also teaches the treatment of IBD that is a fibrotic condition. Palombella teaches “the fibrotic condition is associated with excessive PI3K activity or abnormal activity (e.g., excessive or reduced activity) of one or more components of the PI3K signaling pathway (e.g., Akt (PKB), mTOR, a Tec kinase (e.g., Btk, Itk, Tec), phospholipase C, PDK1, PKCs, NF.kappa.B, Rac GEF (e.g., Vav-1), or Rac). [5111] Thus, clearly there is a connection established between PI3K inhibitors and miltefosine which inhibits phospholipase C, phospholipase D, and protein kinase C. Thus, Palombella teaches the fibrotic conditions including IBD taught by Verhaar and instantly claimed fibrotic diseases are associated with abnormal activity of the PI3K signaling pathway. One would reasonably expect that an immunomodulator that effects this pathway, i.e. miltefosine, taught to treat a fibrotic disorder such as IBD could also be applied to the instantly claimed fibrotic disorders. Weller establishes that miltefosine prevents mast cell degranulation and both Verhaar and Weller teach miltefosine inhibits proinflammatory cytokines.Palombella teaches the PI3K inhibitor prevents mast cell degranulation.
Regarding applicant’s argument that Palombella teaches a PI3K inhibitor in combination with other agents, as discussed above, the combination of references is directed to why one expect miltefosine to treat other fibrotic diseases including instantly claims species. The fact that Palombella teaches other agents is irrelevant. However, it is noted that the instant claims recite comprising language and can include other active agents. In fact the instant application itself teaches IBD and the instantly claimed inflammatory condition are related and IBD was carved out in response to the prior art cited.
Applicant argues that Palombella teaches the unpredictably of a PI3K inhibitors and only compound 292 was effective. Palombella teaches “The role of PI3Ks in TLR signaling is not clear from the literature” and further investigates compound 292. Although 292 is taught to be effective, the reference does not equate this to mean only compound 292 is effective. Again the rejection is based on the combination of references and not the teachings of Palombella in a vacuum. As discussed above, Verhaar teaches miltefosine mechanism of action in treating IBD and Palombella and Weller are relied upon to establish why one would expect miltefosine to treat other fibrotic disorders.
Applicant argues Verhaar teaches the use of immunomodulators to treat IBD is limited and appreciates one assume any immunomodulator can treat any inflammatory condition.
Verhaar concludes that miltefosine inhibits T cell proliferation and effectively reduces inflammation. The above discussion of the mechanism of action taught be Verharr are incorporated herein. Thus, Verhaar concludes that a specific immunomodulator, miltefosine, reduces inflammation and has an immunomodulatory effect by reducing cytokine activity. Palombella is cited to show that IBD along with the claimed inflammatory diseases are fibrotic disorders linked to a pathway and why one would have a reasonable expectation that miltefosine would treat other fibrotic conditions other than IBD. Thus, the rejection is not based on administering miltefosine to any inflammatory disease as argued; rather inflammatory conditions related to IBD.
Applicant alleges that treating each and every inflammatory disorder is unpredictable and one cannot assume immunomodulator work on all inflammatory conditions. Again it is noted that applicant carved out IBD out of the inflammatory conditions claimed. Applicant claims several inflammatory conditions with the administration of miltefosine at one dosage range for all conditions. The rejections of record clearly indicate a mechanism of action of miltefosine that would suggest the treatment of the claimed inflammatory disorders. However, if there is such a high degree of unpredictability of applying immunomodulators to treat inflammatory disorders, then one would assume there are enablement issues with the assumption that one dosage range would treat all the claimed disorders.
Applicant argues that substituting miltefosine into Palombella’s teachings would destroy the teachings of Palambella. Again, the rejection is not based on substitution rather, would one expect success in administering miltefosine to the claimed inflammatory diseases.
Applicant alleges that Harder, Sanini and Chaturvedi do not remedy the alleged deficiencies in Verhaar. However, as applicant’s arguments above were not persuasive, this argument is not persuasive.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP §§ 706.02(l)(1) - 706.02(l)(3) for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 116, 118-120, 126, 128-133, 136-138 and 143-153 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-23 of U.S. Patent No. 9,949,996 in view of Verhaar et al (2013, Inflamm. Bowel Dis., 19(9): 1974-1982), Weller et al (2009, J Invest Dermatol., 129(2):496-8) and Sundar et al (2003, Pediatr Infect Dis J., 22: 434–8).
Just as the instant claims, Patent ‘996 claims treating inflammatory conditions by administering an NKT-2 activator that is a sulfatide along with a RAR agonist. Patent ‘996 does not teach also including miltefosine.
Verhaar is drawn to the use of immunomodulators for the treatment of inflammatory bowel disease, and specifically the immunomodulator miltefosine (see abstract). Verhaar teaches administering 50 mg/kg miltefosine twice weekly to mice with symptoms of inflammatory bowel disease, and Verhaar teaches this treatment alleviating their symptoms (see abstract and page 1975). Verhaar teaches that miltefosine works to inhibit T-cell activation and proliferation and that it is used to treat a variety of inflammatory conditions in humans (see pages 1974-1975). Verhaar teaches the miltefosine treatment significantly reduced proinflammatory cytokines IL-6, TNF-alpha and interferon (see col. 1 on page 1981).
Weller teaches that miltefosine dose dependently 5 - 25 µM (2 - 10 µg/mL), inhibited inhibition of TNF release and mast cell degranulation in vitro, with a maximal effect at 25 µM (10 µg/mL) (see page 496, col. 3 on page 497, col. 1 on page 498, and Figure 1). Weller teaches these effects of miltefosine appears not to be limited to IgE-dependent activation nor to histamine release but also comprises alternative IgE-independent activation pathways and release of cytokines (see col. 1 on page 498). Weller teaches that these results provide proof-of-concept that miltefosine also inhibits inflammatory responses in vivo and indicates that agents such as miltefosine, have the potential as new therapeutics for the treatment of mast cell driven diseases (see col. 1 page 497).
Sundar teaches results of a Phase I/II dose ranging study of miltefosine treatment, wherein subjects were given doses 1.5 mg/kg/day (Group A) and 2.5 mg/kg/day (Group B) (see abstract). Sundar teaches the mean plasma concentration of miltefosine in the treated subjects was 15.8 µg/mL (range of 7 to 31 µg/mL) for 1.5 mg/kg/day dose Group A and 26 µg/mL (range of 4.1 to 69 µg/mL) for 2.5 mg/kg/day dose Group B (see page 437). Sundar teaches that while generally both dose of 1.5 mg/kg/day (Group A) and 2.5 mg/kg/day (Group B) were well tolerated, as per the adult experience, gastrointestinal adverse events were seen: 33 and 39% of children experienced vomiting and 5 and 17% experienced diarrhea in Groups A and B, respectively (see abstract and Table 3).
It would have been obvious to combine Patent ‘996 with Verhaar in view of Weller and Sundar to use Verhaar’s miltefosine with Patent ‘996’s treatment. A person of ordinary skill in the art would have had a reasonable expectation of success in administering miltefosine with Patent ‘996’s treatment because Verhaar teaches that it can be administered to treat inflammatory conditions. The skilled artisan would have been motivated to use miltefosine with Patent ‘996’s because Verhaar teaches that it can be administered to treat inflammatory conditions.
It would have been obvious to further combine Patent ‘996 with Verhaar and Weller with Sundar to treat the subject with is 0.1 to 4 mg/kg, 0.2 to 0.5 mg/kg, 0.2 to 1 mg/kg, 0.5 to 3 mg/kg, 0.5 to 1 mg/kg, 1 to 3 mg/kg, or 2 to 3 mg/kg miltefosine per day in the treatment. A person of ordinary skill in the art would have had a reasonable expectation of success in treating the subjects the treatment with these doses because Verhaar establishes that miltefosine is a useful treatment in mammals and humans, and Sundar provides results of a Phase I/II dose ranging study of miltefosine treatment, wherein subjects were given doses 1.5 mg/kg/day or 2.5 mg/kg/day, and that such doses were generally well tolerated. Furthermore, Sundar establishes that such doses provide subjects with plasma concentration of miltefosine that Weller’s in vitro data show are effective for achieving the desired results of preventing mast cell degranulation and inhibiting TNF release. Additionally, a person of ordinary skill in the art would also have had a reasonable expectation of success in treating the subject in the treatment because Sundar’s results show that even subjects that were given doses 1.5 mg/kg/day provided subjects with plasma concentrations of miltefosine that Weller’s in vitro data show are higher than what is effective for achieving the desired results of preventing mast cell degranulation and inhibiting TNF release, therefore there is a reasonable expectation of success to reduce the dose amount. The skilled artisan would have been motivated to treat the subject in the method with such dose because Sundar provides results of a Phase I/II dose ranging study of miltefosine treatment, wherein subjects were given doses 1.5 mg/kg/day or 2.5 mg/kg/day, and that such doses were generally well tolerated, and, Sundar establishes that such doses provide subjects with plasma concentrations of miltefosine that Weller’s in vitro data show are higher than what is needed for achieving the desired results of preventing mast cell degranulation and inhibiting TNF release, therefore providing motivation to use lower doses than those exemplified in Sundar. Furthermore, Sundar teaches that adverse gastrointestinal events did occur at higher frequency when subjects were given higher doses, therefore providing further motivation to use lower doses than those exemplified in Sundar. It is further obvious to modify the dose since Sundar establishes that giving subjects identical dose results in variable plasma concentrations, thereby providing additional motivation to optimize the dose to achieve a plasma level that achieves the desired effect. Finally, it is noted that the dosing amount is result effective as the references teach that the desired effects of the treatment are dose dependent.
Regarding claim 138, repetition of steps previously recited within a claim is on its own not inventive because it merely requires employing the well-known maxim, “If at first you don’t succeed, try, try again.” See Perfect Web Techs., Inc. v. InfoUSA Inc., 92 U.S.P.Q.2d 1849, 1856 (Fed. Cir. 2009). Repeating steps until a desired result is achieved requires only common sense and is, therefore, not inventive. Id. at 1854-55 (citing KSR Int’l Co. v. Teleflex Inc., 82 U.S.P.Q.2d 1385 (U.S. 2007)).
Claims 116, 118-120, 126, 128-133, 136-138 and 143-153 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 of U.S. Patent No. 10,925,886 in view of Verhaar et al (2013, Inflamm. Bowel Dis., 19(9): 1974-1982), Weller et al (2009, J Invest Dermatol., 129(2):496-8) and Sundar et al (2003, Pediatr Infect Dis J., 22: 434–8).
Just as the instant claims, Patent ‘886 claims treating inflammatory conditions by administering an NKT-2 activator that is a sulfatide along with a RAR agonist. Copending Patent ‘886 does not teach also including miltefosine.
Verhaar is drawn to the use of immunomodulators for the treatment of inflammatory bowel disease, and specifically the immunomodulator miltefosine (see abstract). Verhaar teaches administering 50 mg/kg miltefosine twice weekly to mice with symptoms of inflammatory bowel disease, and Verhaar teaches this treatment alleviating their symptoms (see abstract and page 1975). Verhaar teaches that miltefosine works to inhibit T-cell activation and proliferation and that it is used to treat a variety of inflammatory conditions in humans (see pages 1974-1975). Verhaar teaches the miltefosine treatment significantly reduced proinflammatory cytokines IL-6, TNF-alpha and interferon (see col. 1 on page 1981).
Weller teaches that miltefosine dose dependently 5 - 25 µM (2 - 10 µg/mL), inhibited inhibition of TNF release and mast cell degranulation in vitro, with a maximal effect at 25 µM (10 µg/mL) (see page 496, col. 3 on page 497, col. 1 on page 498, and Figure 1). Weller teaches these effects of miltefosine appears not to be limited to IgE-dependent activation nor to histamine release but also comprises alternative IgE-independent activation pathways and release of cytokines (see col. 1 on page 498). Weller teaches that these results provide proof-of-concept that miltefosine also inhibits inflammatory responses in vivo and indicates that agents such as miltefosine, have the potential as new therapeutics for the treatment of mast cell driven diseases (see col. 1 page 497).
Sundar teaches results of a Phase I/II dose ranging study of miltefosine treatment, wherein subjects were given doses 1.5 mg/kg/day (Group A) and 2.5 mg/kg/day (Group B) (see abstract). Sundar teaches the mean plasma concentration of miltefosine in the treated subjects was 15.8 µg/mL (range of 7 to 31 µg/mL) for 1.5 mg/kg/day dose Group A and 26 µg/mL (range of 4.1 to 69 µg/mL) for 2.5 mg/kg/day dose Group B (see page 437). Sundar teaches that while generally both dose of 1.5 mg/kg/day (Group A) and 2.5 mg/kg/day (Group B) were well tolerated, as per the adult experience, gastrointestinal adverse events were seen: 33 and 39% of children experienced vomiting and 5 and 17% experienced diarrhea in Groups A and B, respectively (see abstract and Table 3).
It would have been obvious to combine Patent ‘886 with Verhaar in view of Weller and Sundar to use Verhaar’s miltefosine with Patent ‘886’s treatment. A person of ordinary skill in the art would have had a reasonable expectation of success in administering miltefosine with Patent ‘886’s treatment because Verhaar teaches that it can be administered to treat inflammatory conditions. The skilled artisan would have been motivated to use miltefosine with Patent ‘886’s because Verhaar teaches that it can be administered to treat inflammatory conditions.
It would have been obvious to further combine Patent ‘886 with Verhaar and Weller with Sundar to treat the subject with is 0.1 to 4 mg/kg, 0.2 to 0.5 mg/kg, 0.2 to 1 mg/kg, 0.5 to 3 mg/kg, 0.5 to 1 mg/kg, 1 to 3 mg/kg, or 2 to 3 mg/kg miltefosine per day in the treatment. A person of ordinary skill in the art would have had a reasonable expectation of success in treating the subjects the treatment with these doses because Verhaar establishes that miltefosine is a useful treatment in mammals and humans, and Sundar provides results of a Phase I/II dose ranging study of miltefosine treatment, wherein subjects were given doses 1.5 mg/kg/day or 2.5 mg/kg/day, and that such doses were generally well tolerated. Furthermore, Sundar establishes that such doses provide subjects with plasma concentration of miltefosine that Weller’s in vitro data show are effective for achieving the desired results of preventing mast cell degranulation and inhibiting TNF release. Additionally, a person of ordinary skill in the art would also have had a reasonable expectation of success in treating the subject in the treatment because Sundar’s results show that even subjects that were given doses 1.5 mg/kg/day provided subjects with plasma concentrations of miltefosine that Weller’s in vitro data show are higher than what is effective for achieving the desired results of preventing mast cell degranulation and inhibiting TNF release, therefore there is a reasonable expectation of success to reduce the dose amount. The skilled artisan would have been motivated to treat the subject in the method with such dose because Sundar provides results of a Phase I/II dose ranging study of miltefosine treatment, wherein subjects were given doses 1.5 mg/kg/day or 2.5 mg/kg/day, and that such doses were generally well tolerated, and, Sundar establishes that such doses provide subjects with plasma concentrations of miltefosine that Weller’s in vitro data show are higher than what is needed for achieving the desired results of preventing mast cell degranulation and inhibiting TNF release, therefore providing motivation to use lower doses than those exemplified in Sundar. Furthermore, Sundar teaches that adverse gastrointestinal events did occur at higher frequency when subjects were given higher doses, therefore providing further motivation to use lower doses than those exemplified in Sundar. It is further obvious to modify the dose since Sundar establishes that giving subjects identical dose results in variable plasma concentrations, thereby providing additional motivation to optimize the dose to achieve a plasma level that achieves the desired effect. Finally, it is noted that the dosing amount is result effective as the references teach that the desired effects of the treatment are dose dependent.
Regarding claim 138, repetition of steps previously recited within a claim is on its own not inventive because it merely requires employing the well-known maxim, “If at first you don’t succeed, try, try again.” See Perfect Web Techs., Inc. v. InfoUSA Inc., 92 U.S.P.Q.2d 1849, 1856 (Fed. Cir. 2009). Repeating steps until a desired result is achieved requires only common sense and is, therefore, not inventive. Id. at 1854-55 (citing KSR Int’l Co. v. Teleflex Inc., 82 U.S.P.Q.2d 1385 (U.S. 2007)).
Response to Arguments
Applicant's arguments filed 12/3/20258 have been fully considered but they are not persuasive.
Applicant relies on their arguments above to traverse these rejections. Further, applicant requests the rejections be held in abeyance. However, as discussed above and incorporated herein, these arguments are not persuasive.
Conclusion
No claims are free of the art. No claims are allowed.
Correspondence Information
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 SHARMILA G. LANDAU whose telephone number is (571)272-0614. The examiner can normally be reached Monday-Friday 7-3:30. 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 supervisor, Jennifer Michener can be reached at 571-272-1424. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/SHARMILA G LANDAU/Supervisory Patent Examiner, Art Unit 1653
Prosecution Insights