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 .
Priority
Acknowledgement is made of the Applicant’s claim for domestic priority based on the U.S. Provisional Application No. 63/434103, filed on December 21, 2022.
Information Disclosure Statement
The informational disclosure statement (IDS) filed on December 20, 2023 is acknowledged and has been considered.
Status of the Claims
Acknowledgement is made of the original claims 1-12, in the instant application No. 18/391,649. Claims 1-12 represent all the claims that are currently under consideration.
Claim Rejections - 35 USC § 112b
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 6, 10-12 are 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.
Regarding claim 6, it is drawn towards a method wherein lenalidomide is used to reduce; “cell-related HIV RNA in HIV patients in PBMC’s derived from HIV patients in vitro”. The phrases, “in HIV patients” and “PBMCs derived from HIV patients in vitro” (emphasis added), renders the instant claim unclear because the limitation is addressing the use of lenalidomide in HIV patients and it also recites PBMC’s derived from the patients in vitro. The term in vitro is well understood in the field to refer to studies conducted outside a living organism, typically in a controlled environment such as a test tube or cell culture system or in a laboratory. In addition, the claim 6 is dependent on claim 5 which recites “wherein lenalidomide is used to reduce the cell-related HIV RNA in HIV patients.” Thus, the claim language in the dependent claim 6 makes the instant invention ambiguous. Applicant needs to make the necessary amendment so that the scope of the claimed invention is clearly defined.
Regarding, claim 10, Applicant claims, “a method for reducing intracellular P24 and cell-related HIV RNA in PBMCs derived from HIV patients in vitro with lenalidomide comprising orally administering lenalidomide” (emphasis added). The claim is directed towards reducing the said intracellular P24 and HIV RNA derived from HIV patients in vitro. As discussed in the previous paragraph, the term in vitro implies this is done outside a living organism, like in a laboratory. The claim further recites orally administering lenalidomide, and goes on to recite the dosage of lenalidomide. As written, the oral administering of lenalidomide at the given dosage, appears to be administered to the PBMCs that are derived from the HIV patients. There is no clear indication that the oral administration of lenalidomide is to a patient. As such, the claim language is confusing to one of ordinary skill in the art. Applicant needs to make the necessary amendment to remove ambiguity in the claimed invention.
Regarding claim 11, Applicant claims a method of inhibiting latent activator-induced activation of; “latent HIV cell line U1 with lenalidomide, comprising orally administering lenalidomide”, (emphasis added). The invention recites U1 which is a known chronically HIV-1 infected human cell line. It further recites, comprising orally administering lenalidomide. The term ‘oral administering’ is not usually directed to cell line studies and thus the claimed invention is ambiguous.
Additionally, the instant claim further recites the dosage of lenalidomide; “orally administering lenalidomide at 25 mg/d at days 1 to 21 in a 28-day cycle and continuing ART for 48 weeks”. Examiner notes that the claim does not mention the administering is to a patient. As such the steps outlined in the claim appear to be directed to the U1 cell line. The phrase “oral administering” may imply to a patient but the claim does not disclose that. Thus, the language of the claim is ambiguous and applicant needs to amend so that the invention is definite and clear enough for someone of ordinary skill in the art to understand the boundaries of the invention.
Claim 12 is a further limitation of the latent activator in claim 11, and so incorporates all other limitations of claim 11. Thus, it is referencing the ambiguity recited in claim 11 as discussed above. The phrases that render claim 11 ambiguous also render claim 12 ambiguous. Applicant needs to make the necessary amendments so that the metes and bounds of the claimed invention are clear.
Claim Rejections - 35 USC § 112d
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 6 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Applicant’s independent claim 1 recites a method that is drawn towards administering a therapeutic amount of lenalidomide, “to a patient” while claim 6, a dependent of claim 5 which depends on claim 1, is directed toward using lenalidomide in PMBC’s derived from HIV patients in vitro. Claim 6 broadens the claimed invention beyond the scope of a patient as recited in parent claim 1.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-6 are rejected under 35 U.S.C. 102(a)1 as being anticipated by Pourcher et al., 2017, (Publication for Clinical Trial NCT01282047; Phase II Trial of Lenalidomide in HIV-Infected Patients with Previously Treated Kaposi’s Sarcoma: Results of the ANRS 154 Lenakap Trial; started 2011-08, completed 2014-02. Published in Aids Res. Hum. Retroviruses, Vol. 33, No.1, page 1-10). hereon after, Pourcher.
Claim interpretation: For the purpose of enabling compact prosecution and applying prior art, claims 6, a dependent of claim 5 which is a dependent of claim 1, is examined with the considering that lenalidomide is administered to a HIV patient; wherein lenalidomide is used to achieve the recited limitation in the instant claim in a HIV patient
Regarding “wherein”, applicant’s claims 3-6 recite the following "wherein"
limitations: "wherein lenalidomide is used to reduce Th1 inflammatory cytokines in peripheral blood and cerebrospinal fluid of HIV patients" (claim 3), "wherein lenalidomide is used to relieve chronic inflammatory state in HIV patients" (claim 4), " wherein lenalidomide is used to reduce cell-related HIV RNA level in HIV patients" (claim 5), "wherein lenalidomide is used to reduce intracellular P24 and cell-related HIV RNA in PBMCs derived from HIV patients in vitro" (claim 6).
The determination of whether a wherein clause is a limitation in a claim depends on the specific facts of the case. In Hoffer v. Microsoft Corp., 405 F.3d 1326, 1329, 74 USPQ2d 1481, 1483 (Fed. Cir. 2005), the court held that when a "whereby clause states a condition that is material to patentability, it cannot be ignored in order to change the substance of the invention." However, the court noted (quoting Minton v. Nat'l Ass'n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)) that a "whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.” Id. Accordingly, under Hoffer, consistent with Minton, the wherein clause in the instant Applicant's method claims are properly not given weight when it simply expresses the intended result of a process step positively recited, namely, reducing Th1 inflammatory cytokines in peripheral blood and cerebrospinal fluid of HIV patients, relieving chronic inflammatory state in HIV patients, reducing cell-related HIV RNA level in HIV patients, or reducing intracellular P24 and cell-related HIV RNA in PBMCs derived from HIV patients in vitro.
Thus, Applicant’s wherein clauses in claims 3-6 are properly not given patentable weight since they simply express an intended use of a process step positively recited, namely, administering lenalidomide to a patient with AIDS.
Regarding claims 1-6, Pourcher teaches a phase II clinical trial was conducted to study the efficacy and safety of lenalidomide in HIV-infected patients previously treated Kaposi’s Sarcoma (KS), with a plasma viral load <50 copies/ml and a median CD4 cell count of 444 mm3. He teaches, lenalidomide is a second-generation thalidomide derivative approved in patients with certain cancers; an oral immunomodulating drug, that is more potent and avoids many of the serious adverse effects including neuropathy and that it is well tolerated in antiretroviral experienced patients (abstract and page 2). The instant claim 2 recites a lenalidomide dosage administered orally in a 28-day cycle with ART continued for 48 weeks. Pourcher teaches patients received combined antiretroviral therapy (ART) for at least twelve months and a lenalidomide dosage of 25 mg on days 1-21 followed by a 7-day wash-out period every 28 days for 24 weeks. The administration of lenalidomide was continued for a further 12 weeks in case of complete response in patients or for 24 weeks in case of partial response – all patients were followed until week 48 (page 2).
Claims 3-6 are drawn towards lenalidomide reducing inflammatory cytokines (claim 3), chronic inflammatory state (claim 4), reducing cell related HIV RNA in HIV patients (claim 5) and reducing intracellular P24 and cell-related HIV RNA (claim 6). Pourcher discloses lenalidomide was used to treat Kaposi’s Sarcoma in HIV infected patients a condition that is associated with chronic inflammation in a context of immunodepression (page 7). He teaches lenalidomide has antiangiogenic, direct antitumoral and immunostimulatory properties, inhibiting TNF-α, IL-1, IL-6, IL-12 and vascular endothelial growth factor (VEGF) expression and increases IL-8, IL-10 and IFN-γ production. Pourcher discloses increase in plasma IL-8 levels, reflect T-cell activation induced by lenalidomide (pages 2-8). Thus, Pourcher anticipates claims 1-6.
In addition, Claims 1-6 are rejected under 35 U.S.C. 102(a)1 as being anticipated by Polizzotto et al., 2015, (Polizzotto et al., “Leveraging Cancer Therapeutics for the HIV Cure Agenda: Current Status and Future Directions.” Drugs, 75, page 1447-1459; Published, 30 July 2015), hereon after, Polizzotto.
In the instant invention, applicant claims a method of promoting functional cure of AIDS by reducing HIV reservoir with lenalidomide and by administering lenalidomide to a patient orally at the recited dosage (claims 1-2), wherein lenalidomide is used to reduce certain HIV associated conditions in the patients as recited in claims 3-6.
Polizzotto teaches persistence of an HIV reservoir in long-lived immune cells has been a barrier to its eradication or cure but that many cancer therapies have dual utility in targeting the HIV reservoir (page 1447). He informs artisans that established therapeutic strategies in oncology are likely to contribute agents with potential to have impact on HIV latency; that many of the pathways implicated in maintenance of viral latency and persistence of cellular reservoirs are highly conserved and have been implicated either in oncogenesis or in the immune response to malignancies. He further discloses that these agents are potentially attractive not only because they target cell types and pathways implicated in HIV persistence, but because their toxicity and pharmacokinetic profiles are already established (page 1450).
From Polizzotto’s teachings, thalidomide and its derivatives (IMIDs), lenalidomide (CC-5013) and pomalidomide (CC-4047), are small molecules with broad-based effects on immune activation, including T-cell activation and responsiveness, as well as anti-angiogenic properties. He teaches many of their activities are mediated through binding to and inactivation of cereblon, an E3 ubiquitin ligase with multiple targets that is highly expressed in lymphocytes and their immunologic effects are well characterized including effects that may influence the HIV reservoir. According to his teachings, IMIDs have been shown in vitro to augment T-cell responsiveness and proliferation by several mechanisms, leading to increased production of IL-2 and interferon-γ (IFN-γ), inhibition of pro-inflammatory cytokine and chemokine production, and they also enhance CD4- and CD8-positive T-cell co-stimulation (page 1454).
Polizzotto references a Clinical trial NCT01057121 (2010-2014), whose primary objective was to determine the maximum tolerated dose of lenalidomide in subjects with AIDS-related Kaposi’s sarcoma, and where patients received lenalidomide orally once daily on days 1-21 with treatment repeated every 28 days for up to 12 courses, with the recommended dosage being 25 mg /day. In addition, the secondary objectives of the referenced clinical trial included evaluating the effects of lenalidomide on HIV plasma viral loads, determining the effects of lenalidomide on T-lymphocyte subset including natural killer cells, assessing changes in natural killer cell number (PBMC and tumor) and function pre-and post-lenalidomide. Teachings from the referenced clinical trial disclose plasma cytokines trended towards less inflammatory pattern (Section 5.2-page 1454). Accordingly, the teachings of Polizzotto anticipate claims 1-6.
Therefore, claims 1-6 were anticipated by prior art.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-9 are rejected under 35 U.S.C. 103 as being unpatentable over Polizzotto et al., 2015, (Polizzotto et al., “Leveraging Cancer Therapeutics for the HIV Cure Agenda: Current Status and Future Directions.” Drugs, 75, page 1447-1459; Published, 30 July 2015), hereon after Polizzotto, in view of Balasko and Keynan, 2019, (Balasko, A. and Keynan, Y., “Shedding light on IRIS: from Pathophysiology to Treatment of Cryptococcal Meningitis and Immune Reconstitution Inflammatory Syndrome in HIV-Infected Individuals”, HIV Medicine, 20, pages 1-10; Published 10 August 2018), hereon after, Balasko.
Claim interpretation: The claim interpretations set forth in the previous section above are hereby incorporated into the instant rejection. Any additional claim interpretations are set forth below.
Regarding claim 9; Incorporated herein are claim interpretation in the previous section above regarding, the “wherein’ limitation. Applicants claim 9 recites, “wherein after lenalidomide administration”. The limitation following the lenalidomide administration, i.e., “inflammatory cytokines in the peripheral blood and CSF of the patients are detected and PBMCs are extracted to detect intracellular HIV RNA level of the patients”, simply expresses the intended result of a process step positively recited, which step is lenalidomide administration. Thus, inflammatory cytokines in the peripheral blood and the CSF of the patients detected, and the intracellular HIV RNA levels extracted from PBMCs are all as a result of the administration of lenalidomide. Accordingly, the wherein clause is properly not given patentable weight since it simply expresses the result of lenalidomide administration to the said patient.
In the instant claims 1-9, Applicant claims a method for promoting functional cure of AIDS by reducing HIV reservoir with lenalidomide in patients by administering lenalidomide, and a further limitation wherein the patients are HIV patients with persistent central inflammation after screening of HIV-related cryptococcal meningitis and the patients still have central damage after receiving anti-fungal therapy.
Regarding claims 1-6, the teachings of Polizzotto as set forth in the above 35 U.S.C. 102 Rejections, are incorporated herein.
Polizzotto’s teachings explain that lenalidomide is an oral immunomodulatory drug with potent anti-inflammatory, anti-angiogenic and immunomodulatory properties hence it was studied in clinical trials for patients with HIV associated Kaposi sarcoma. The teachings reveal that Kaposi sarcoma occurs in individual with advanced HIV and in some patients there is a condition termed as Kaposi sarcoma immune reconstitution syndrome (KS-IRIS); that the immunomodulatory properties of lenalidomide could address both the impaired cellular immunity and inflammation associated with KS in patients. From the clinical trial conducted with lenalidomide, proinflammatory cytokines decreased while the anti-inflammatory cytokines and immune stimulating T cells increased. (Page 1454, under 5.2, Ref Clinical Trial NCT01057121).
The prior art differs from the instant claims as follows: While Polizzotto teaches that lenalidomide is administered to patients with HIV associated Kaposi sarcoma, he does not specifically teach on HIV patients with persistent central inflammation after screening of HIV-related cryptococcal meningitis and wherein the patients still have central damage after receiving standard antifungal therapy, elevated cerebrospinal fluid (CSF) protein level and plasma HIV RNA of < 50 copies/ ml and CD4 T cell count of > 100 cells/mm3 after receiving ART for at least 48 weeks as recited in the instant claims 7-9.
Regarding claims 7-9, Balasko teaches cryptococcal meningitis (CM), develops in individuals with a CD4 T-cell count of < 50 cells/ µL, but has been seen in cases of CD4 count > 200 cell/ µL; that the immunocompromised state of HIV-infected individuals resulting from predominantly type 2 T helper (Th2) /Th17 biased responses in CM, rather than Th1, correlates with increased inflammation (page 2 - CM Pathophysiology and manifestation). This leads to the development of immune reconstitution inflammatory syndrome (IRIS) which presents exaggerated and deregulated proinflammatory immune reaction in the immunocompromised late-stage HIV infected patients who have commenced ART.
Further, Balasko teaches concerning treatment of CNS IRIS in HIV infected patients with CM that anti-TNF-α antagonists are the more effective therapeutic treatments when targeting IRIS and thalidomide has been used to treat HIV-infected patients. She discloses several examples of HIV-CM IRIS patients who were successfully treated with thalidomide (page 7 -Future therapeutics options).
Her teachings reveal thalidomide, a TNF-α cytokine antagonist, as the current immunomodulatory treatment, available for use against HIV-CM CNS IRIS. It has been shown to decrease Th1 overreaction and restore immune balance. She also informs artisans that thalidomide causes severe side effects, significant birth abnormalities and so it is not used in expecting mothers; and that despite its side effects, it is a treatment that is applicable to many HIV-infected patients with cryptococcal meningitis such as nonexpecting females and male patients (page 7).
Per MPEP § 2143 (I) )(A) and (B), a prima facie case of obviousness exists (i) for combining prior art elements according to known methods and (ii) for simple substitution of one known element for another, to obtain predictable results. Polizzotto teaches that both thalidomide and lenalidomide are immunomodulatory drugs with anti-angiogenesis, immunosuppressive and anti-inflammatory activity. He discloses that cancer therapies offer attractive pathways for HIV treatment because in addition to their pharmacological and toxicity profiles which are established, they generally have a path to licensure through their primary oncology indications. Additionally, prior art teaches that despite thalidomide’s therapeutic properties, it is associated with high toxicity and congenital abnormalities, thus its use is restricted from certain populations.
Therefore, regarding the instant claims 1-9, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant application to combine the teachings Polizzotto and Balisko; to substitute lenalidomide for thalidomide in the treatment of HIV patients with persistent central inflammation after screening of HIV-related CM with a reasonable expectation of success. One would have been motivated to do so because lenalidomide, a derivative of thalidomide, is known to be effective and safe for individuals with HIV infection, the oral dosage and cycle recited in the instant invention is already a known FDA-approved dosage for treatment for patients with HIV related malignancies and lenalidomide is known to have safer side effects as compared to thalidomide.
Claims 10-12 are rejected under 35 U.S.C. 103 as being unpatentable over Makonkawkeyoon et al. 1993, (Makonkawkeyoon et al., “Thalidomide inhibits the replication of human immunodeficiency virus type 1.” Proc. Natl. Acad. Sci. USA, vol. 90, No. 13, pages 5974-5978; Published, July 1993), hereon after, Makonkawkeyoon in view of Saloura and Grivas, 2010, (Saloura V. and Grivas P. D. (2010), “Lenalidomide: a synthetic compound with an evolving role in cancer management” – Review Article, Hematology, Vol 15, No 5, pages 318-331, Published 22 January, 2010), hereon after, Saloura.
Claim interpretation: Claims 10-12 have a 112b Rejection above, however for the purpose of compact prosecution and in the light of prior art, Examiner applied the following interpretation. The instant claims are drawn towards a method of reducing intracellular p24 and HIV RNA in PMBCs derived from HIV patients in vitro with lenalidomide, comprising orally administering lenalidomide at the said dosage while continuing ART for 48 weeks (claim 10); inhibiting latent activator induced activation of latent HIV cell line U1 with lenalidomide, comprising orally administering lenalidomide at the said dosage while continuing ART for 48 weeks (claim 11) and claim12 further limits the latent activator in claim 11 to TNF-α, PMA or LPS.
For the purpose of examination, the claims are given the broadest reasonable interpretation consistent with the specification. Accordingly, the limitation in claim 10, “a method for reducing intracellular p24 and cell-related HIV RNA in PBMCs derived from HIV patients in vitro” was considered as an in vitro step. Likewise, in claim 11, the “method for inhibiting latent activator-induced activation of latent HIV cell line U1 with lenalidomide” was considered as a step carried out in the cell line U1. The parts in both claims that recite “comprising orally administering lenalidomide at 25 mg/d at days 1 to 21 in a 28-cycle and continuing ART for 48 weeks” were interpreted as separate steps, i.e., conducted separately from the in vitro steps and not as subsequent steps as currently seems implied in the claims as recited.
Regarding claims 10-12, Makonkawkeyoon teaches artisans of studies carried out to evaluate the effect of thalidomide on the PBMCs of patients with HIV-1 infection and AIDS; studies on cell lines obtained from 17 HIV-1+ donors evaluated by p24 Ag ELISA. Results from the study reveal inhibition of HIV-1 activation in peripheral blood mononuclear cells (PMBCs) of 16 out of 17 patients with advanced HIV-1 infection and AIDS. Thus, thalidomide a selective inhibitor of TNF-α production by monocytes, significantly reduces HIV-1 replication in PBMCs for HIV-1 infected hosts and in agonist -stimulated latently infected cell line (Table 4 & Discussion, page 5977). His teachings reveal that studies conducted demonstrate that thalidomide inhibits TNF-α mRNA levels and TNF-α protein as well as the expression of HIV-1 in infected cell lines and inhibit HIV-1 activation in PBMCs of infected patients.
Makonkawkeyoon further teaches thalidomide, as a selective inhibitor of tumor necrosis factor α (TNF-α) synthesis, suppresses the activation of latent HIV-1 in a monocytoid (U1) line. He teaches the inhibition to be dose dependent and occurs after exposure of the cells to TNF-α, phorbol myristate acetate (PMA), lipopolysaccharide (LPS) and other cytokine combinations. He discloses that associated with HIV-1 inhibition is a reduction in agonist induced TNF-α protein and mRNA production. He further reveals thalidomide inhibition of virus replication in PMA- and recombinant TNF-α-stimulated T-cell line ACH-2 is not observed (abstract). He informs artisans that thalidomide selectively inhibits the production of human peripheral blood mononuclear cell (PMBC) TNF-α when the cells are induced in vitro with lipopolysaccharide (LPS) and other agonists. He concludes that the results from his teachings suggest the use of thalidomide in a clinical setting to inhibit both virus replication and TNF-α-induced systemic toxicity of HIV-1 and opportunistic infections (page 5974).
The prior art differs from the instant claims as follows - Makonkawkeyoon teaches on thalidomide and not lenalidomide.
Saloura teaches lenalidomide (CC-5013, REVLIMID®) is a functional and structural analog of thalidomide with a relatively benign toxic profile and pleiotropic anti-tumor activity exhibiting anti-angiogenic and immunomodulatory effects (Abstract). His teachings reveal that when compared with thalidomide, lenalidomide has enhanced T-cell and CD8 cell activation and enhanced IL-2 and IFN-γ production, activates natural killer (NK) cells, it’s a more potent inhibitor of TNF-α and has weaker antiangiogenic effects. Thus, his review discloses lenalidomide is more potent and less toxic compared to thalidomide and demonstrates lower rates of neurologic side effects (sedation, neuropathy) (pages 318-320, 325-330).
Thus, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant application to substitute lenalidomide with thalidomide to arrive at the instant claims 10-12 with reasonable expectation of success. A skilled artisan would have been motivated to do so because lenalidomide as functional derivative of thalidomide has been used to treat the same diseases that thalidomide treats; it is a more potent TNF-α inhibitor with enhanced T-cell proliferation and safer side effects as compared to thalidomide.
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 § 2146 et seq. 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 filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual 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/apply/applying-online/eterminal-disclaimer.
Claims 1-4 and 7-8 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 7, 10 and 12 of copending Application No. 18/391,645 (hereon after, ‘645), alone or in view of Pourcher et al., 2017, (Publication for Clinical Trial NCT01282047; Phase II Trial of Lenalidomide in HIV-Infected Patients with Previously Treated Kaposi’s Sarcoma: Results of the ANRS 154 Lenakap Trial; started 2011-08, completed 2014-02. Published in Aids Res. Hum. Retroviruses, Vol. 33, No.1, page 1-10), hereon after, Pourcher, and further in view of Balasko and Keynan, 2019, (Balasko, A. and Keynan, Y., “Shedding light on IRIS: from Pathophysiology to Treatment of Cryptococcal Meningitis and Immune Reconstitution Inflammatory Syndrome in HIV-Infected Individuals”, HIV Medicine, 20, pages 1-10; Published 10 August 2018) hereon after, Balasko. Although the claims at issue are not identical, they are not patentably distinct from each other.
Regarding the instant claims 1 and 7, Claim 1 in the copending application, ‘645, claims a method of improving or treating cognitive dysfunction caused by HIV associated cryptococcal meningitis (CM) immune reconstitution inflammatory syndrome (IRIS) in a patient with lenalidomide. In the instant application, lenalidomide is administered to patients with HIV AIDs (claim 1) and further limitation to HIV patients with persistent central inflammation after screening for HIV-related CM (claim 7). The claims in the instant application are drawn to same patient population as the copending claim 1. It is assumed that administering lenalidomide to the same patient population would be expected to produce the same result, therefore claims 1 in the copending application renders claims 1 and 7 in the instant application obvious.
Regarding instant claim 2, directed towards lenalidomide oral dosage; claims 2-4 in ‘645 recite identical limitations; claim 2 recites lenalidomide is administered for 6 treatment cycles comprising of 21 days of lenalidomide and 7 days of no lenalidomide; claim 3 recites the dosage of 25 mg/day and claim 4 recites treatment with lenalidomide is carried out on a basis of continuing antiretroviral therapy (ART) and anti-cryptococcal treatment. In the instant claim 2 the lenalidomide dosage of 25 mg/day is administered in a 28-day cycle and ART is continued for 48 weeks. Although the instant claim 2 and the copending application claim 2-4, are not exactly identical, they are not patentably distinct from each because they disclose identical dosage of lenalidomide administered to HIV infected patients. Pourcher discloses lenalidomide is an FDA-approved drug (REVLIMID®) with a prescribed oral dosage of 25 mg/ day administered daily on days 1-21 in a 28-day cycle. Thus, claims 2-4 in the copending application ‘645 alone, or further in view of Pourcher render claim 2 in the instant application obvious.
Regarding instant claims 3, and 4, claims 1, 7, 10 and 12 in ‘645 are directed to improving or treating cognitive dysfunction caused by HIV associated CM IRIS in a patient with lenalidomide (claim 1), wherein the patient has chronic inflammation of the central system (claim 7), wherein the treatment is not useful for patients with neutrophil count ≤ 1000 cell/ µL or less and a platelet count < 75,000/ µL (claim 10) and wherein the treatment reduces the recited cytokines, proteins and inflammatory cytokines (claim 12).
Claims 3 and 4 in the instant application are drawn towards lenalidomide reducing Th1 inflammatory cytokines in peripheral blood and cerebrospinal fluid in HIV patients and to relieve chronic inflammatory state in HIV patients. Additionally, Pourcher informs artisans that lenalidomide is an immunomodulatory drug with antiangiogenic and immunostimulatory properties and thus inhibits TNF-α, interleukin(IL)-1, IL-6, IL-12 and vascular endothelial growth factor and increases IL-8, IL-10 and IFN-γ production.
In referencing recommendations for lenalidomide prescription, Pourcher discloses that that patients with neutrophil count < 1000 cell/ µL and a platelet count < 75,000/ µL, among other conditions are not eligible to receive lenalidomide. Accordingly, claims 1,7,10 and 12 in copending application ‘645 and further in view of Pourcher’s teachings are targeting very similar patient population as the instant claim 3 and 4. . It is understood that administering lenalidomide to similar patient population would be expected to produce the same result .Thus claims 1, 7, 10 and 12 render the instant claims 3 and 4 obvious.
Regarding the instant claim 8, Claim 1 in the copending application, ‘645, is drawn towards a method of improving or treating cognitive dysfunction caused by HIV associated CM-IRIS in a patient with lenalidomide. Balasko’s teaches CNS infection in HIV infected patients is related to T-cell immunosuppression and CM develops in individuals with a CD4 T-cell count of < 50 cells/µL, and in some cases of CD4 count > 200 cells/µL (page 2 CM pathophysiology and manifestation). Balasko informs artisans of two known forms of CM-IRIS - unmasking IRIS and paradoxical IRIS. Among the symptoms for unmasking IRIS is an altered mental state including personality and behavioral changes, confusion and hallucinations. Paradoxical CM IRIS is also attributed to symptoms of altered mental state due to raised intracranial and cerebrospinal fluid pressure.
The instant claim 8 recites a limitation wherein the patients still have central damage after receiving standard anti-fungal therapy, elevated cerebrospinal fluid protein level and plasm HIV RNA of < 50 copies/ ml and CD4 T cell count of > 100 cells / mm3 after receiving ART for 48 weeks.
Balasko’s teachings render obvious that patients with cognitive dysfunction caused by HIV-associated CM IRIS as recited in ‘645 claim 1 are not different from HIV-patient population in the instant claim 8. Accordingly, claim 8 in the instant application and claim 1 in ‘645, although not identical, they are not patentably distinct from each other because lenalidomide is administered as method to treat HIV infected patients with CM and persistent central damage. It can be assumed that administering the same drug to patients recited in the two limitations will be produce the same results because the patient populations in both claims read into each other. Thus, claim 1 in copending application renders claim 8 in the instant application obvious.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claim is found to be allowable.
Communication
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/P.O./Examiner, Art Unit 1627
/Kortney L. Klinkel/Supervisory Patent Examiner, Art Unit 1627
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