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 Arguments
Applicant’s response, together with the document titled “Verified translation of Annexes I-II” of Chen Xi (“Xi translation”) is acknowledged.
Claim Rejections - 35 USC § 112
Applicant’s claim amendments overcome the rejection of record, in view of which it is hereby withdrawn.
Claim Rejections - 35 USC § 103
Applicant’s arguments have been carefully considered, but have not been found to be persuasive.
Applicant has amended the claims, and made arguments against the claims as amended.
PNG
media_image1.png
160
714
media_image1.png
Greyscale
First, it is noted that Applicant’s new claimed features were previously addressed with respect to dependent claims.
Applicant’s response provides:
PNG
media_image2.png
562
690
media_image2.png
Greyscale
In response, Applicant has argued against the references individually. As an initial matter the Examiner reminds Applicant that it is impermissible to attack references singly when the Examiner relies upon the combined teachings of the references, nor may they attack a reference for not teaching a limitation of the claim when the Examiner has explicitly relied upon another reference as teaching that limitation. See In re Kotzab, 217 F.3d 1365, 1370 (Fed. Cir. 2000)).
In the instant case, it is noted that the bolded paragraph stating that “the treatment method of incomplete immune reconstruction in AIDS is also completely different from the treatment of AIDS” is not understood, and Applicant provides no support for this position either. Since incomplete immune reconstruction occurs in AIDS patients, and is an aspect of the disease, treating this immune reconstitution in AIDS patients is a part and parcel of treating AIDS itself. Second, Applicant has argued that HAART therapy can achieve good immune reconstitution, but that not all HIV-infected people can achieve good immune reconstitution. This statement is vague too, because it suggests that all HIV-infected people can achieve it, but it is not as good in some as it is in others. Further, this issue completely aside, it is noted that Li discloses the broad genus of triptolide derivatives of Formula (I), which have been isolated from Tripterygium Wilfordii Hook f (Lei Gong Teng)—i.e. not compounds of another class, but precisely the claimed class-- to include Applicant’s specifically claimed compound LLDT-8, as well as LLDT-2, for which (the latter) Liu does disclose that it treats incomplete immune reconstitution and that it enhances CD4 counts.
Further, Applicant has made arguments with respect to the book Annex 1: Medicinal Chemistry, 7th edition, 2021. Applicant’s response provides:
PNG
media_image3.png
208
696
media_image3.png
Greyscale
PNG
media_image4.png
544
682
media_image4.png
Greyscale
PNG
media_image5.png
210
694
media_image5.png
Greyscale
In response, the Examiner would like to set the record straight. First of all, the translation provided is with reference to three full pages, but nonetheless solely provides just this very limited translation. With respect to two full pages it just provides this.
PNG
media_image6.png
264
600
media_image6.png
Greyscale
Then with respect to another full page, it just provides this.
PNG
media_image7.png
216
596
media_image7.png
Greyscale
Looking at the first part, it is noted that what is being referred to is drug metabolism of progesterone. So, this is not activity, this is metabolism. Further, triptolide, or (5R)—5-hydrotripolide, are not progesterones. They diterpenoid epoxides derived from the plant Tripterygium Wilfordii Hook f (Lei Gong Teng), and are structurally unrelated to progesterone. Applicant address neither the fact that these are drugs of a different class, not the fact that the translation reference to metabolism, not activity, and that there is nothing of record to show that the compounds in Annex 2. Then the second part refers to two completely different compounds, from even the first two that the first two that Applicant’s translation referred to, which do not even have -OH substitution as in Applicant’s claimed compound. Then it refers to some activity (it is not even said vis-à-vis what), and notes that they have a difference of activity for this completely different compounds. It is hard to understand what the parallels to the instant compounds are at all.
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 17-26, 29, 31 and 32 are rejected under 35 U.S.C. 103 as obvious over US 2007/0197476 A1 to Li et al. (also published as CN 1511838 A), and further in view of Liu et al., Immune activation and incomplete immune reconstitution in chronic human immunodeficiency virus infected patients, Medical Journal of Peking Union Medical College Hospital, 2017, p. 100-104, Vol. 8, No. 4-5 (“Liu”), and Marziali et al., T-cell homeostasis alteration in HIV-1 infected subjects with low CD4 T-cell count despite undetectable virus load during HAART, AIDS 20(16): p 2033-2041, October 24, 2006 (“Marziali”).
Claim interpretation
The Examiner incorporates her understanding of Applicant’s claims from the 35 U.S.C. 112(b) rejection above.
Rejection
Li discloses triptolide derivatives of Formula (I), which have been isolated from Tripterygium Wilfordii Hook f (Lei Gong Teng).
PNG
media_image8.png
122
205
media_image8.png
Greyscale
(Abstract, [0002]).
It specifically discloses as a compound of the genus Applicant’s claimed compound (5R)-5-hydroxytriptolide (LLDT-8). Of note, it also discloses triptolide (which is LLDT-2 of Li, discussed further below). Li provides the structures of both.
PNG
media_image9.png
212
284
media_image9.png
Greyscale
(p. 8 of the original document).
It also discloses numerous studies with it, to include inhibition of ConA induced T-lymphocyte proliferation, inhibition of LPS induced B-lymphocyte proliferation, prevention and treatment of arthritis (Example 2, [0022], [0039], [0042], [0050-57], [0110]). It also discloses that LLDT-8 decreased the production of IL-12, TNF-. and IL-6, but increased IL-10 production from Sac-activated lymphocytes. ([0131]). “The results suggest that LLDT-8 exhibit inhibitory effects not only on cell-mediated immune responses, but also on humoral-mediated immune responses.” ([0166]).
Li specifically claims a composition with the triptolide derivatives, to specifically include LLDT-8, and a method of treating a number of diseases with an underlying immune pathology, to specifically include among them AIDS, comprising administering a pharmaceutical composition of the triptolide derivative in an effective dosage to a patient. "8. A method of treating at least one of autoimmune diseases, including arthritis, systemic lupus erythematosus, chronic nephritis, diabetes and inflammatory diseases, including AIDS, virus hepatitis, and allergies and skin diseases, and cardiovascular diseases, and transplant rejections, and anti-fertility and immune related diseases which comprises administrating the pharmaceutical composition of claim 7.“ (claims 1, 6 and 8, [0036]). Li further specifically singles out LLDT-8 as a lead compound for this treatment. "[0222] The derivatives in the present invention, especially LLDT-8, or their combinations can be explored as immunosuppressant for prevention and therapy against autoimmune diseases (arthritis, systemic lupus erythematosus, chronic nephritis, diabetes); inflammatory diseases (AIDS, virus hepatitis); allergy; skin diseases, cardiovascular diseases and transplant rejection, as well as anti-fertility and immune related diseases." This list discloses diseases with chronic abnormal immune activation. The composition with the triptolide derivatives is claimed as the sole active ingredient. (claim 7).
Per Li, triptolide derivatives, their pharmaceutically acceptable salts or optically active isomers of the invention may be made into a variety of therapeutic dosage forms which contain active components from 0.001 to 99.9% (weight) and appropriate pharmaceutically acceptable carriers for oral, parenteral and intestine administration. ([0035]). A person of skill in the art would know an oral therapeutic dosage form to include a solid tablet.
Thus, since Li explicitly discloses administering LLDT-8 in a pharmaceutically effective amount for treating AIDS, this will necessarily result in treating or preventing (a disease of) incomplete immune reconstitution associated with (chronic and/or NF-B related) abnormal immune activation in AIDS patient, and will enhance CD4 counts in these patients. This is because a compound and its properties are inseparable. The claiming of an unknown property that is inherently present in the prior art does not make the present claims patentable. See In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977).
Further, administering to the HIV infected population necessarily encompasses the subcomponent population of immunologic nonresponders (which is up to about 40% of the total population) with incomplete immune reconstitution. Thus, Li alone anticipates Applicant’s claims 17-20, 24-26, 29 and 30, or at a minimum, renders them prima facie obvious.
Li does not specifically disclose that the HIV patients have been on ART for a specific duration, their CD counts and measuring them, and the daily dose of the drug, per Applicant’s claims as amended.
Liu discloses that among the studies of intervention on immune activation in HIV infected adults, an in vitro experiment and a clinical trial have indicated that Tripterygium Wilfordii Hook f (TWHF) could suppress the abnormal immune activation, and may improve the immune reconstitution state in HIV-infected patients. Liu specifically discloses that TWHF can inhibit Toll-like receptors and NF-B signaling pathways, and inhibit PMBCs from HIV infected patients from producing a number of pro-inflammatory cytokines. Liu also discloses parallel studies with triptolide compounds isolated from TWHF (e.g. triptolide, which is LLDT-2 of Li). Liu also discloses administering TWHF to HIV-infected individuals. Per Liu, the results suggest that after treatment with adequate amounts of TWHF for chronic HIV-infected patients with incomplete immune reconstitution, the CD4+ T cell count increased significantly, and the activation levels of CD4+ and CD8+ T cells decrease. Liu concludes that both in vitro data and clinical trials suggest that TWHF may inhibit the immune activation of HIV-infected patients and increase the CD4+ T cell count of patients with chronic HIV infection and incomplete immune reconstitution.
PNG
media_image10.png
570
538
media_image10.png
Greyscale
(p. 5).
Liu discloses that common recognized definition of immunological non-responders is taking HAART treatment for at least 2 years, complete virus suppression for at least one year, CD4+ T cell counts < 200 cells/ ml, or CD4+ T cells increase less than 20% from baseline. (p. 2). This disclosure of at least 2 years on ART renders obvious Applicant’s claim limitations of at least 3 years and at least 4 years on ART, because AIDS is known in the art to be a chronic disease with no complete cure as of yet, and with ongoing life time treatment. Similarly, as <200 cells/µL is equivalent to <200 cells/mm³, this disclosure further renders obvious Applicant’s claim limitations requiring CD counts below <350 cells/mm³.
Liu does not explicitly discloses that the measurements of CD4+ cells are done using flow cytometer in vitro. Liu does not note, however, references 4-7 with respect to the disclosure above pertaining to numbers of CD4+ cells. Turning to the first one, Marziali, it pertains to an investigation of the pathogenesis of low CD4 T-cell counts in HIV subjects who are immunological non responders (InR) to HAART. (Abstract). The Materials and methods section reveals that this measuring of CD4+ cells was done by way of flow cytometry in vitro. (p. 2035, col. 2).
Accordingly, it would have been obvious to a person of skill in the art before the effective filing date of the claimed invention to combine the teachings of Li, Liu and Marziali in order to practice Applicant’s claimed invention with a reasonable expectation of success. The skilled artisan would have been motivated to do so since Li specifically claims a composition with the triptolide derivatives, to specifically include LLDT-8, and a method of treating a number of diseases with an underlying immune pathology, to specifically include among them AIDS, comprising administering a pharmaceutical composition of the triptolide derivative in an effective dosage to a patient. The skilled artisan would have been further motivated to do so, because Liu specifically further specifically discloses further proof-of-concept studies, and concludes that both in vitro data and clinical trials suggest that TWHF (to include by way of data with specific triptolide compounds isolated from it) may inhibit the immune activation of HIV-infected patients and increase the CD4+ T cell count of patients with chronic HIV infection and incomplete immune reconstitution. Further motivation to do so is because both references disclose that the instant compound is isolated from TWHF, and that a lead compound of Li- LLDT-2 (but with lesser activity than LLDT-8), is also an active compound in Liu with specific activity in HIV patients. Even though Li does not specifically disclose the specific daily dose, since it notes it to be a result-effective variable, it would have been obvious to a person of skill in the art before the effective filing date of the claimed invention to determine the specific daily dose of the drug for the purpose of enhancing CD4+ counts and treating or preventing a disease of incomplete immune reconstitution in AIDS in a subject in need thereof.
Other relevant art
The Examiner also restates for the record the following relevant prior art over which no rejections were made solely in view of its cumulative nature.
-Zhou et al., Inhibition of inducible nitric-oxide synthase expression by (5R)-5-hydroxytriptolide in interferon-gamma- and bacterial lipopolysaccharide-stimulated macrophages, J Pharmacol Exp Ther, 2006 Jan;316(1):121-8 (“Zhou”, of record)
Zhou discloses: “(5R)-5-Hydroxytriptolide (LLDT-8) is a novel analog of triptolide that has antiarthritic, hepatoprotective, and antiallogenic transplantation-rejective effects. In the present study, we report that LLDT-8 inhibited nitric oxide (NO) production and inducible nitric-oxide synthase (iNOS) expression in macrophages. LLDT-8 significantly attenuated NO production, in a dose-dependent manner, in primary peritoneal macrophages and a macrophage cell line of Raw 264.7 cells following stimulation with interferon (IFN)-gamma, lipopolysaccharide (LPS), and IFN-gamma plus LPS. It also reduced the production of tumor necrosis factor-alpha from LPS-stimulated Raw 264.7 cells. To further elucidate the mechanism responsible for the inhibition of NO, we examined the effect of LLDT-8 on IFN-gamma and LPS-induced iNOS expression. Indeed, LLDT-8 prevented NO generation by inhibiting iNOS expression at mRNA level and protein level, rather than by interfering its enzymatic activity. In IFN-gamma-stimulated Raw 264.7 cells, LLDT-8 suppressed the gene transcription of signal transducer and activator of transcription 1alpha and interferon regulatory factor (IRF)-1, but it displayed no apparent effect on IFN-gamma receptor level on cell surface. After LPS challenge, LLDT-8 further abrogated the expression of LPS receptor complex, including CD14, Toll-like receptor 4, and myeloid differentiation protein-2; decreased the LPS-induced phosphorylation of stress-activated protein kinase/c-Jun NH(2)-terminal kinase, extracellular signal-regulated kinase 1/2, and p38 mitogen-activated protein kinase (MAPK); retarded the degradation of IkappaBalpha; and ameliorated the DNA binding activity of nuclear factor-kappaB (NF-kappaB) to nuclear proteins that accounts for transcriptional regulation of iNOS. Taken together, these results suggest that LLDT-8 reduces NO production and iNOS expression by inhibiting IFN-gamma-triggered IRF-1 expression and LPS-triggered MAPK phosphorylation and NF-kappaB activation.”
-CN 103083334A (“CN ‘334”, of record)
CN ‘334 relates to the application of TWHF and its main ingredient triptolide (LLDT-2 of Li) to inhibit excessive immune activation and inflammation in patients with HIV/ AIDS, which is mainly used to treat incomplete immune reconstruction and non-AIDS-related HIV/ AIDS disease, to include inhibiting excessive CD4+ T-lymphocyte markers of HIV. ([0007], [0015]).
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 SVETLANA M IVANOVA whose telephone number is (571)270-3277. The examiner can normally be reached 8:30-5:00.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Kortney L. Klinkel can be reached on (571) 270-5239. 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.
/SVETLANA M IVANOVA/ Primary Examiner, Art Unit 1627
Prosecution Insights