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
This Application filed on 11/20/2024 is a CON of PAT 12201626 (17/041,800) filed on 09/25/2020 which is a 371 of PCT/IB2019/05513 filed on 06/19/2019 and claims priority to AUSTRALIA 2018902181 filed on 06/19/2018.
Claim Status
Claims 27-43 are pending and under examination.
The rejections are as below:
Claim Rejections - 35 USC § 112 – 2nd Paragraph
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.
"The primary purpose of this requirement of definiteness of claim language is to ensure that the scope of the claims is clear so the public is informed of the boundaries of what constitutes infringement of the patent. A secondary purpose is to provide a clear measure of what applicants regard as the invention so that it can be determined whether the claimed invention meets all the criteria for patentability and whether the specification meets the criteria of 35 U.S.C. 112, first paragraph with respect to the claimed invention.", (see MPEP § 2173).
Claims 27-43 are rejected under 35 U.S.C. 112, second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which applicant regards as the invention.
Applicants have amended independent claim 1 to recite the limitations “…selectively inducing apoptosis in proliferating cancer cells…” and “…wherein the administration has selective toxicity to actively dividing cancer cells”.
Claim 1 requires an active method step of administering to “the subject” [a subject having cancer] a composition comprising a therapeutically effective amount of pyronaridine (PND) once, twice, three, four or five times daily or every second or third day, or once every week, or once every two weeks, wherein the therapeutically effective amount of PND is at least 100 mg.
Applicants admit that PND is in fact NOT selective to all cancer cells. For example, Applicants teach the SCI values (<1) were not favourable on T47D and HCC-70 breast cancer cell lines with values below 1 (Figure 5). They also teach PND exhibited poor selectivity for the CEM cell line and poor selectivity (<2.0) on the pancreatic and lung cancer lines (Figure 5). See Specification at [00108] and Figure 5. Thus, it is unclear how the limitations “…selectively inducing apoptosis in proliferating cancer cells…” and “…wherein the administration has selective toxicity to actively dividing cancer cells” are intended to limit the claims. For example, it is unclear if these limitations limit the cancer being treated, the amount of PND administered, the timing of PND administration, or something else entirely. It is further unclear if these limitations mean that the administered PND is does not induce apoptosis in and/or is not toxic to any other cell in the body of the subject administered PND.
Furthermore, Applicants’ method of determining “selectivity” as it applies to “selectively inducing apoptosis” or “selective toxicity” is flawed because Applicants merely divided the CC50 against a non-cancer cell line (MCF-10A) by the CC50 against a cancer cell line. However, the CC50 against a non-cancer cell line was 6.6 mM, which clearly indicates toxicity against this cell line. This does not indicate “selectivity” against cancer cell lines as Applicants propose. It merely shows that PND had different CC50s against different cell lines. All Applicants’ data shows is that PND is cytotoxic to both normal and cancer cells with varying degrees of cytotoxic activity. If PND selectively induced apoptosis in proliferating cells or had selective toxicity to actively dividing cells, its CC50 against a non-cancerous cell line would be much higher than 6.6 mM. As such, it is totally unclear what “…selectively inducing apoptosis in proliferating cancer cells…” and “…wherein the administration has selective toxicity to actively dividing cancer cells” even means and by what objective metric such selectivity should be determined.
Alternatively, it is unclear if the limitations “…selectively inducing apoptosis in proliferating cancer cells…” and “…wherein the administration has selective toxicity to actively dividing cancer cells” should be construed as merely reciting an intended result of carrying out the method step recited in the claims, i.e., are non-limiting to the claims. For example, if the prior art teaches or suggests an active method step of administering to “the subject” [a subject having cancer] a composition comprising a therapeutically effective amount of pyronaridine (PND) once, twice, three, four or five times daily or every second or third day, or once every week, or once every two weeks, wherein the therapeutically effective amount of PND is at least 100 mg, it could be reasonably construed to meet all of the patentable limitations of the claim. Put differently, the biological results of administering the same active agent to the same subject population in the same dosing regimen are inherent properties of such administration.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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 27-43 are rejected under 35 U.S.C. 103(a) as being unpatentable over US 2011/0300137 A1 (Published 12/08/2011) and CN1280826A (Published 01/24/2001) (English Translation Provided and referenced below) in view of QI ET AL. (Biochemical and Biophysical Research Communications, 2004, vol. 319, pages 1124-1131) and ASADI-POOYA ET AL. (Medical Hypothesis, 2007, vol. 69, pages 560-563).
The amended claims drawn to methods of selectively inducing apoptosis in proliferating cancer cells for the treatment of cancer in a subject, the method comprising the step of administering to the subject a composition comprising a therapeutically effective amount of pyronaridine (PND), or a pharmaceutically acceptable salt thereof, once, twice, three, four or five times daily or every second or third day, or once every week, or once every two weeks, wherein the therapeutically effective amount of PND, or pharmaceutically acceptable salt thereof, is at least about 100 mg, and the PND, or pharmaceutically acceptable salt thereof, induces said apoptosis, wherein the method does not include administration of another chemotherapeutic agent and wherein the administration has selective toxicity to actively dividing cancer cells. See Claims 1 and 34.
US ‘137 teaches the use of the anti-malarial drug lumefantrine and related compounds in the treatment of cancer. See Abstract. See also [0009] (“Lumefantrine, currently used in treatment of malaria, has utility in the treatment of cancer either used alone and as part of combination therapy with another drug. Other compounds related to lumefantrine by structure and/or by their use in ACTs, have utility in the treatment of cancer either used alone and as part of combination therapy with another drug.”) “[R]elated compounds” include pyronaridine. See [0007] (“[S]everal other compounds have been used as alternatives to lumefantrine in formulating ACTs for treating malaria…These include…pyronaridine”). See also [0022] (“Specific examples of lumefantrine-alternative drugs in ACTs which also have utility in treating cancer include…pyronaridine...[L]umefantrine-alternative drugs may be used in cancer treatment either alone, or as part of a combination therapy with an ER stressor drug.”) Dose ranges of the composition administered to a patient can be from about 0.5 to 1000 mg/kg of the patient’s body weight and may be a single dosage or series of two of more given in the course of one or more days, as need by the patient. See [0023]. For specific compounds where human dosages for treatment of at least some condition have been established, the present invention will use those same dosages. Id. The daily dosage regimen for an adult human patient may be, for example, an oral dose of between 0.1 mg and 6000 mg of each ingredient, preferably between 1 mg and 5000 mg, e.g. 25 to 5000 mg. See [0024]. Suitably the compounds will be administered for a period of continuous therapy, for example for a week or more, or for months or years. Id. Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the modulating effects, or minimal effective concentration (MEC). See [0025]. Compositions should be administered using a regimen that maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%. See [0026]. Regarding combination therapy as recited in Claims 9-12, it teaches the present invention relates to the use of a lumefantrine-alternative drug or a pharmaceutically acceptable salt thereof, together with an ER stressor drug in a synergistic effective dose. See [0032]. Examples of suitable drug classes that function as ER stressor drugs include, inter alia, the claimed gemcitabine. See [0021]. Regarding Claims 6-8, it discloses the pharmaceutical compositions and methods provided in the present invention are particularly deemed useful for the treatment of substantially the same cancers recited in the instant claims. See [0042].
US ‘137 expressly claims:
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See Claims 17-23.
Thus, while disclosing pyronaridine as a lumefantrine-alternative drug that may be used in cancer treatment either alone, or as part of a combination therapy with an ER stressor drug, US ‘137 does not provide any working examples demonstrating the anti-cancer activity of pyronaridine in vitro or in vivo.
CN ‘826 teaches the use of pyronaridine in the preparation of antitumor drugs and drugs for reversing tumor multidrug resistance ([0001] of provided English Translation). It teaches the antimalarial drug, pyronaridine, has an anti-tumor effect and an apparent MDR effect of reversing tumors ([0006] of provided English Translation). It teaches pyronaridine (PND) inhibited human leukemia cells K562, H160 and human solid tumor cells MCF-7, KB, A549 cells, indicating that PND has a wide range of anti-tumor activity in vitro, and can be made into anti-tumor drugs ([0009] and Table 1 of provided English Translation). It teaches as a PND for the treatment of malaria drugs, its clinical dose is iv. 3 ~ 6mg/kg, can even reach 10mg/kg, twice a day, the highest blood concentration can reach 50 ~ 100μg/ml, far higher than the maximum in vitro reversal dose of 4.40μM in the use of the invention ([0012] of provided English Translation). It teaches the administration routes are oral and intravenous ([0013] of provided English Translation). It teaches a tablet comprising 100 mg (0.1 g) of pyronaridine (Example 1). It expressly claims the use of pyronaridine and its salts in the preparation of antitumor drugs (Claim 1).
QI ET AL. teach pyronaridine (PND) is a novel modulator of P-glycoprotein-mediated multidrug resistance in tumor cells in vitro and in vivo (Title; Abstract). They provide in vitro IC50s for PND against numerous cancer cell types, including myeloid leukemia, epidermoid carcinoma, breast carcinoma, ovarian carcinoma, gastric carcinoma, colon carcinoma, hepatocellular carcinoma.
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See Table 1. They teach administering PND via i.p injection at a dose of 20, 40, 60, 80, or 100 mg/kg, q3d for four injections and orally (via p.o.) at a dose of 40, 60, 80, or 100 mg/kg every day (qd) x 3, every 5 days for three cycles to normal female BALB/c mice to determine maximum tolerated dose (MTD).1 See page 1125, right paragraph, last paragraph. They teach administering 40 mg/kg PND (i.p., q3d for four injections) or PND at 20, 40, or 60 mg/kg, p.o., qd x 3, every 5 days for three cycles in combination with doxorubicin to mice bearing K562 or K562/A02 (myeloid leukemia) xenografts (page 1126, left column, first paragraph). They demonstrate that administration of PND in combination with doxorubicin has anti-tumor activity in vivo (Fig. 4).
The combined teachings of the cited prior art clearly suggest administering pyronaridine (PND) to mammals having cancer. Indeed, Qi et al. expressly teach that administration of PND to mammals (mice) having cancer (K562 or K562/A02 myeloid leukemia xenografts) has anti-tumor activity. Qi et al. also demonstrate that PND is cytotoxic to numerous cancer cells in vitro, with IC50s ranging from 8.3 to 21.4 M. A person of ordinary skill in the art at the time the application was filed would have had a reasonable expectation that administering PND once, twice, three, four, or five times daily or every second or third day, or once every week, or once every two weeks in an amount of at least 100 mg to a subject having cancer would be therapeutically effective given the known cytotoxic activity of PND against numerous cancer cell lines in vitro and the demonstrated anti-tumor activity of PND in vivo.
Further regarding administration of PND once, twice, three, four, or five times daily or every second or third day, or once every week, or once every two weeks in an amount of at least 100 mg, the combined teachings of the cited prior art provide the general conditions for administering PND to mammals having cancer. Indeed, US ‘137 disclose dose ranges of the composition administered to a patient can be from about 0.5 to 1000 mg/kg of the patient’s body weight and may be a single dosage or series of two of more given in the course of one or more days, as need by the patient. See [0023]. The daily dosage regimen for an adult human patient may be, for example, an oral dose of between 0.1 mg and 6000 mg of each ingredient, preferably between 1 mg and 5000 mg, e.g. 25 to 5000 mg. See [0024]. Suitably the compounds will be administered for a period of continuous therapy, for example for a week or more, or for months or years. Id. US ‘137 teaches for specific compounds where human dosages for treatment of at least some condition have been established, the present invention will use those same dosages [0023]. Qi et al. teach administering PND daily or every 3 days to mammals having cancer. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.") Here, although the claims are not limited to human subjects, the claimed “at least 100 mg” falls squarely within the human dose range taught in US ‘137, i.e., an oral dose of between 0.1 mg and 6000 mg of each ingredient, preferably between 1 mg and 5000 mg, e.g. 25 to 5000 mg. See [0024]. Further, ASADI-POOYA ET AL. is cited as evidence of the known human therapeutic dosages of pyronaridine (PND). Asadi-Pooya et al. teach the dosage of PND recommended for treatment of human malaria has been shown to be very safe, without significant adverse-effects in humans. The drug can be given orally, intramuscularly, and intravenously. The recommended total oral dosage is 1200 mg divided into 3 or 4 doses and administered over three days. See page 562, left column, first paragraph. Accordingly, administering PND in the known therapeutic dosages as suggested by US ‘137 (“…for specific compounds where human dosages for treatment of at least some condition have been established, the present invention will use those same dosages”), e.g., orally administering a dosage of 1200 mg divided into 3 or 4 doses and administered over three days, to human subject having cancer would have been prima facie obvious and would be an amount and dosing falling within the scope of the claimed “at least about 100 mg” administered “once, twice, three, four, or five times daily or every second or third day”.
For at least the above reasons, the claimed method is prima facie obvious over the combined teachings of the cited prior art.
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 27-43 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of U.S. Patent No. 12201626B2. Although the claims at issue are not identical, they are not patentably distinct from each other because both set of claims are drawn to a method of selectively inducing apoptosis in proliferating cancer cells for the treatment of cancer in a subject, the method comprising the step of administering to the subject a composition comprising a therapeutically effective amount of pyronaridine (PND), or a pharmaceutically acceptable salt thereof, once, twice, three, four or five times daily or every second or third day, or once every week, or once every two weeks, wherein the therapeutically effective amount of PND, or pharmaceutically acceptable salt thereof, is at least about 100 mg, and the PND, or pharmaceutically acceptable salt thereof, induces said apoptosis, wherein the method does not include administration of another chemotherapeutic agent and wherein the administration has selective toxicity to actively dividing cancer cells, while the claims herein are selectively administered once every four weeks, and can be administered with a chemotherapeutic agent. The claims are anticipated over ‘626.
Conclusion
Applicant is requested to specifically point out the support for any amendments made to the disclosure in response to this Office action, including the claims (M.P.E.P. §§ 714.02 and 2163.06). In doing so, applicant is requested to refer to pages and line (or paragraph) numbers (if available) in the as-filed specification, not the published application. Due to the procedure outlined in M.P.E.P. § 2163.06 for interpreting claims, other art may be applicable under 35 U.S.C. § 102 or 35 U.S.C. § 103(a) once the aforementioned issue(s) is/are addressed.
Applicant is reminded that MPEP §2001.06(b) clearly states that “[t]he individuals covered by 37 C.F.R. 1.56 have a duty to bring to the attention of the examiner, or other Office official involved with the examination of a particular application, information within their knowledge as to other copending United States applications which are "material to patentability" of the application in question." See Armour & Co. v. Swift & Co., 466 F.2d 767, 779, 175 USPQ 70, 79 (7th Cir. 1972). MPEP §2001.06(b) clearly indicates that “if a particular inventor has different applications pending in which similar subject matter but patentably indistinct claims are present that fact must be disclosed to the examiner of each of the involved applications.” See Dayco Prod. Inc. v. Total Containment, Inc., 329 F.3d 1358, 1365-69, 66 USPQ2d 1801, 1806-08 (Fed. Cir. 2003).
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LAYLA SOROUSH whose telephone number is (571)272-5008. The examiner can normally be reached on Monday thru Friday; 8:30 AM to 5:00 PM PST.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, James Henry Alstrum-Acevedo, can be reached on (571)272-5548. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/LAYLA SOROUSH/ Primary Examiner, Art Unit 1622
1 The dosing schedules were every day (qd) and every 3 days (q3d), thus encompassing the claimed “at least every second or third day”.
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