DETAILED ACTION
Status of the Claims
Claims 1, 3-4, 6-7, 10, 15-16, 18, 20, 22, 24-25, 27-29, 31-33, 35-38, 40-41 and 43-46 are pending in the instant application. Claims 31 and 32 have been withdrawn based upon Restriction/Election. Claims 1, 3-4, 6-7, 10, 15-16, 18, 20, 22, 24-25, 27-29, 33, 35-38, 40-41 and 43-46 are being examined on the merits in the instant application.
Advisory Notice
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
All rejections and/or objections not explicitly maintained in the instant office action have been withdrawn per Applicants’ claim amendments and/or persuasive arguments.
Priority
The U.S. effective filing date has been determined to be 05/22/2018, the filing date of the U.S. Provisional Application No. 62/675,110.
Information Disclosure Statement
The information disclosure statement submitted on 11/17/2025 was filed after the mailing date of the first office action on the merits, however, Applicant has indicated the appropriate fee has been paid. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the Examiner.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1, 3-4, 6-7, 10, 15-16, 18, 20, 22, 24-25, 27-29, 33, 35-38, 40-41 and 43-46 are rejected under 35 U.S.C. 103 as being unpatentable over DESAI (US 2010/0166869; published July, 2010) in view of Houssaini et al. (“Rapamycin Reverses Pulmonary Artery Smooth Muscle Cell Proliferation in Pulmonary Hypertension,” 2013; American journal of respiratory cell and molecular biology, Vol. 48, No. 5, pp. 568-577) and Dou et al. (Sustained delivery by a cyclodextrin material-based nanocarrier potentiates antiatherosclerosis activity of rapamycin vi selectively inhibiting mTORC1 in mice,” 2016, ELSEVIER; Journal of Controlled Release, Vol. 235, pp. 48-62);
and as evidenced by Gasper et al. (“Adventitial Nab-Rapamycin Injection Reduces Porcine Femoral Artery Luminal Stenosis Induced by Balloon Angioplasty via Inhibition of Medial Proliferation and Adventitial Inflammation,” 2013; Circulation: Cardiovascular Interventions, Vol. 6, No. 6, pp. 701-709).
Applicants Claims
Applicant claims a method of treating pulmonary hypertension in a human individual, comprising parenterally administering to the human individual a nab-rapamycin composition, wherein the composition comprises nanoparticles comprising rapamycin and an albumin, wherein the nanoparticle composition is administered intravenously or subcutaneously, wherein the dose of rapamycin in the composition is about 1 mg/m2 to about 10 mg/m2, wherein the composition is administered about once a week, two out of three weeks, or three out of four weeks, wherein the pulmonary hypertension is pulmonary arterial hypertension, and wherein the treatment does not comprise an administration of a taxane, and wherein administration of the composition produces a six-minute walking distance (6MWD) performance in the individual of about 15% or higher after the treatment as compared to the 6 MWD performance in the individual before the administration of the composition (instant claim 1).
Applicant claims a method for improving a six-minute walking distance (6MWD) performance in a human individual having pulmonary arterial hypertension, comprising administering to the individual a nab-rapamycin composition comprising nanoparticles comprising rapamycin and an albumin, wherein the composition is administered intravenously or subcutaneously, wherein the dose of rapamycin in the composition is about 1 mg/m2 to about 10 mg/m2, wherein the composition is administered about once a week, two out of three weeks, or three out of four weeks, wherein the method does not comprise an administration of a taxane (instant claim 43).
Applicant claims a method for treating pulmonary hypertension in a human individual, comprising administering to the human individual a nab-rapamycin composition, wherein the composition comprises nanoparticles comprising rapamycin and an albumin, wherein the composition is administered intravenously or subcutaneously, wherein the dose of rapamycin in the composition is about 1 mg/m2 to about 10 mg/m2, wherein the composition is administered about once a week, two out of three weeks, or three out of four weeks, for at least 16 weeks, wherein the pulmonary hypertension is pulmonary arterial hypertension, wherein the treatment does not comprise administration of a taxane, and wherein administration of the composition produces a six-minute walking distance (6MWD) performance in the individual of about 15% or higher after the treatment as compared to 6MWD performance in the individual before administration of the composition (instant claim 46)
Determination of the scope
and content of the prior art (MPEP 2141.01)
DESAI teaches methods for treating, stabilizing, preventing, and/or delaying pulmonary hypertension by administering nanoparticles that comprise rapamycin or a derivative thereof, and a protein carrier (see whole document, particularly the title and abstract, [0029]-[0030]).
DESAI teaches that: “In yet another aspect, the invention provides a method of treating pulmonary hypertension in an individual by parenterally administering to the individual (e.g., a human) an effective amount of a composition comprising nanoparticles that comprise rapamycin or a derivative thereof and a carrier protein (e.g., albumin such as human serum albumin). The invention also provides a method of treating pulmonary hypertension in an individual by intravenous, intra-arterial, intramuscular, subcutaneous, inhalation, intraperitoneal, nasally, or intra-tracheal administering to the individual (e.g., a human) an effective amount of a composition comprising nanoparticles that comprise rapamycin or a derivative thereof and a carrier protein (e.g., albumin such as human serum albumin).” [emphasis added]([0070])(instant claims 1, 18, 20, 21, 26-27 and 30). DESAI further teaches that: “Exemplary effective amounts of rapamycin or a derivative thereof in the nanoparticle composition include […] about 1 to about 5 mg/m2, about 5 to about 10 mg/m2 […].” [emphasis added]([0070]-[0071])(instant claims 1, 3-4)(MPEP §2144.05-I: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists.”). DESAI discloses the albumin-containing nanoparticle formulation of rapamycin is referred to as Nab-rapamycin ([0025]). DESAI teaches sustained release formulations: “In some variations, sustained continuous release formulation of the composition may be used. In one variation of the invention, nanoparticles (such as albumin nanoparticles) of the inventive compounds can be administered by any acceptable route […].” [emphasis added]([0086]).
Further regarding the dose, DESAI teaches that: “In some variations, the nanoparticle composition is administered over a period of at least one month, wherein the interval between each administration is no more than about a week, and wherein the dose of rapamycin or a derivative thereof and/or a taxane ( e.g., paclitaxel) at each administration is about 0.25% to about 25% of its maximum tolerated dose following a traditional dosing regime. […] about 1 % to about 20% of its maximum tolerated dose following a traditional dosing regime. In some variations, the dose of rapamycin or a derivative thereof per administration is less than about any of 25%, 24%, 23%, 22%, 20%, 18%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1 % of the maximum tolerated dose [MTD].” [emphasis added]([0089]). The examiner notes that the maximum tolerated dose for nab-rapamycin is 100 mg/m3 as evidenced by the instant Specification (p. 8, [0052], last 4 lines) and Gasper et al. (p. 702, col. 2, §Nab-Rapamycin). Therefore, the DESAI suggest a dose of nab-rapamycin of “about 0.25% to about 25% of its maximum tolerated dose” where 0.25 of 100 mg/m2 is 0.25 mg/m2 and 25% is 25 mg/m2, and 1% of the MTD is 1 mg/m2 and 10% of the MTD is 10 mg/m2.
DESAI teaches that: “Exemplary dosing frequencies include, but are not limited to, weekly without break; weekly, three out of four weeks; once every three weeks; once every two weeks; weekly, two out of three weeks. In some variations, the composition is administered about once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 6 weeks, or once every 8 weeks.” ([0073])(instant claims 1 & 10)(MPEP §2144.05-I: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists.”).
DESAI teaches that: “The administration of the composition can be extended over an extended period of time, such as from about a month up to about seven years. In some variations, the composition is administered over a period of at least about any of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 30, 36, 48, 60, 72, or 84 months.” ([0074])(instant claims 40-41).
DESAI teaches that: “In some variations, the albumin to rapamycin weight ratio is about any of 18: 1 or less […].” ([0021], [0022], [0106], [107], [138])(instant claim 29, 33). And further that: “In some variations, the average or mean diameter of the particles is no greater than about 200 nm.” ([0021], [0022], [0108] & claim 16)(instant claim 28). Regarding the claim limitation that “wherein the albumin is complexed with rapamycin.” (instant claim 38), DESAI discloses Nab-rapamycin ([0030]) which is a nanoparticle formulation in which albumin is complexed with rapamycin as evidenced by Gasper et al. disclosing that: “Nab-rapamycin is a novel form of rapamycin complexed with albumin protein to create stable nanoparticles […].” (p. 702, col. 2, §Nab-Rapamycin)(instant claim 39).
DESAI teaches that: “In some variations of any of the above methods of combination therapy, the pulmonary hypertension is pulmonary arterial hypertension (PAH).” ([0054], [0106], [0129], Example 13: [0205]-[0207] and claims 1-3)(instant claim 13). And further teaches that: “Patients with PAH in functional class III or IV on best available therapy have limited therapeutic options. Since implementation of a new organ allocation system, it has become more difficult for functional class IV patients to be transplanted. This study provides a therapeutic that may lead to better treatment options for patients with PAH.” (Example 19: [0235]-[0260]; Example 20: [0261]-[0280])(instant claim 15).
Regarding the claimed “concentration of the mTOR inhibitor in the blood” (instant claims 6-7), DESAI teaches that: “Nab-rapamycin was nontoxic at the highest dose of 180 mg/kg on a q4dx3 schedule. No changes in blood chemistry or CBC were observed. No hypercholesterolemia and hypertriglyceridemia were observed. As illustrated in FIGS. 1 and 2C, Nab-rapamycin exhibited linear pharmacokinetics with respect to dose and rapid extravascular distribution as demonstrated by large Vss and Vz. The Cmax and AUCinf of Nab-rapamycin were dose proportional (FIGS. 2A and 2B, respectively).” ([0163]). The claimed dose (i.e. about 5 mg/m2 to about 10 mg/m2, claims 1, 3-4) being rendered obvious, administration (i.e. subcutaneous) being the same, claimed blood level would have also, more likely than not, been the same as well (MPEP §2112-IV).
DESAI teaches that: “In some variations, class 4 PAH is characterized by, but not limited to, pulmonary hypertension with inability to carry out any physical activity without symptoms, such that patients manifest signs of right heart failure, dyspnoea and/or fatigue may even be present at rest, and discomfort is increased by any physical activity. In some variations, the individual may be NYHA class II or IV despite three months of stable therapy ( e.g., prostacyclin, phosphodiesterase type 5 inhibitor (sildenafil), endothelin receptor antagonist (ambrisenten), or combinations thereof).” ([0059]). And further that: “Patients with severe PAH despite best available therapy are recruited for participation in the clinical study. Target patients are those with severe PAH (NYHA class III or IV) despite best available therapy. Best available therapy includes a Prostacyclin (unless unwilling or unable to tolerate) and at least one oral agent (e.g., an endothelin receptor antagonist and/or phosphodiesterase type 5 inhibitor).” ([0237]). DESAI further teaches inclusion criteria for their clinical trials, including that: “Subjects are included in the study if (1) age> 18 yo with PAH, (2) right heart catheterization diagnosis of PAH: Mean Pulmonary Artery Pressure (mPAP) >25 mmHg at rest, Pulmonary Capillary Occlusion Pressure (PCOP) or Left Ventricular End Diastolic Pressure (LVEDP) <15 mmHg, and Pulmonary Vascular Resistance (PVR) >3 mmHg/L/min, (3) patients must be IPAH, FPAH, or APAH, (4) echocardiographic evidence of Right Ventricular Dysfunction, (5) on standard and stable PAH therapy including: (a) a Prostacyclin (IV epoprostenol, IV or subcutaneous remodulin, inhaled iloprost) unless unwilling or unable to tolerate therapy, (b) phosphodiesterase type 5 inhibitor (sildenafil), ( c) endothelin receptor antagonist (Ambrisenten) or (d) any combination of a-c, (6) NYHA class III or IV despite 3 months of stable therapy, (7) 6 Minute Walk Distance <380 m, (8) negative serum pregnancy test, and (9) female of childbearing age either surgically sterilized or using acceptable method of contraception. Inclusion criteria may vary from the above described criteria (i.e., one or more criteria) as appropriate.” ([0275])(instant claims 24-25; instant claim 1 “wherein the pulmonary hypertension is pulmonary arterial hypertension”).
Regarding the limitation “wherein the treatment does not comprise an administration of a taxane.” (instant claim 1, last two lines), DESAI clearly teaches methods of treating pulmonary hypertension without a taxane, for example DESAI teaches that: “In yet another aspect, the invention provides a method of treating pulmonary hypertension in an individual by parenterally administering to the individual (e.g., a human) an effective amount of a composition comprising nanoparticles that comprise rapamycin or a derivative thereof and a carrier protein (e.g., albumin such as human serum albumin). The invention also provides a method of treating pulmonary hypertension in an individual by intravenous, intra-arterial, intramuscular, subcutaneous, inhalation, intraperitoneal, nasally, or intra-tracheal administering to the individual ( e.g., a human) an effective amount of a composition comprising nanoparticles that comprise rapamycin or a derivative thereof and a carrier protein ( e.g., albumin such as human serum albumin). In some variations, the route of administration is intravenous, intra-arterial, intramuscular, or subcutaneous. In some variations, an effective amount of the composition is administered systemically ( e.g., intravenously) over a period of less than 30 minutes.” [emphasis added]([0077]). Additionally, claims 1-3, 6-10 and 14-19 are directed an a method of treating pulmonary hypertension and do include rapamycin and a protein carrier (albumin - claim 14), and do not include a taxane.
DESAI teaches treating pulmonary arterial hypertension (claim 2) with rapamycin and an albumin protein carrier (claim 14) and teaches Nab-Rapamycin as a species thereof (p. 23, Examples 3)(instant claim 39).
Regarding the limitation “wherein administration of the composition improves a six-minute walking distance (6MWD) performance of the individual (instant claim 1), DESAI clearly teaches the same administration of the same composition Nab-Rapamycin at the same dose ([0070]-[0071]), and the resulting improved walking distance would have also been the same.
MPEP §2112.02-II makes clear that: “The discovery of a new use for an old structure based on unknown properties of the structure might be patentable to the discoverer as a process of using. In re Hack, 245 F.2d 246, 248, 114 USPQ 161, 163 (CCPA 1957). However, when the claim recites using an old composition or structure and the "use" is directed to a result or property of that composition or structure, then the claim is anticipated. In re May, 574 F.2d 1082, 1090, 197 USPQ 601, 607 (CCPA 1978) (Claims 1 and 6, directed to a method of effecting nonaddictive analgesia (pain reduction) in animals, were found to be anticipated by the applied prior art which disclosed the same compounds, as well as a method of using them for effecting analgesia but which was silent as to addiction. The court upheld the rejection and stated that the inventors had merely found a new property of the compound and such a discovery did not constitute a new use. […] "While the references do not show a specific recognition of that result, its discovery by appellants is tantamount only to finding a property in the old composition." 363 F.2d at 934, 150 USPQ at 628 (emphasis in original)).
In the instant case DESAI clearly suggest the same compositions administered by the same method in the same dose, and teaches treating PAH patients, therefore the results of the method would have been the same as those claim, particularly the relative 6MWD performance would have been the same (instant claims 1 and 42 – 6MWD performance).
Ascertainment of the difference between
the prior art and the claims (MPEP 2141.02)
The difference between the rejected claims and the teachings of DESAI is that DESAI does not expressly teach a specific embodiment encompassing the instantly rejected claims. However, the differences are not considered nonobvious because each of the claimed ranges are disclosed in DESAI such that they overlap in scope, such that DESAI fairly suggest treating pulmonary (arterial) hypertension by subcutaneous administration of the same compositions (Nab-rapamycin) in the same amounts.
DESAI teaches that: “Once pulmonary hypertension develops, the right side of the heart works harder to compensate; however, the increased effort causes it to become enlarged and thickened. Proliferation of smooth muscle and endothelial cells which normally exist in a quiescent state leads to remodeling of the vessels with obliteration of the lumen of the pulmonary vasculature.” ([0003]). And further that: “Pulmonary vascular smooth muscle cells undergo a phenotypic switch from contractile normal phenotype to a synthetic phenotype leading to cell growth and matrix deposition. Histological examination of tissue samples from patients with pulmonary hypertension shows intimal thickening, as well as smooth muscle cell hypertrophy, especially for those vessels <l00 µm diameter. Further, abnormal smooth muscle cells often overexpress endotheline and serotonin transporters, which likely play a role in the development of PH.” ([0004]). And further that: “In some variations, any of the methods of treatment provided herein may be used to treat and individual (e.g., human) who has been diagnosed with or is suspected of having pulmonary hypertension. In some variations, the individual may be a human who exhibits one or more symptoms associated with pulmonary hypertension. In some variations, the methods of treatment provided herein reduce pulmonary pressure. In some variations, the methods of treatment provided herein inhibit and/or reduce abnormal cell proliferation in the pulmonary artery. In some variations, the abnormal cell proliferation is abnormal cell proliferation of smooth muscle and endothelial cells.” ([0060]).
Houssaini et al. teaches rapamycin reverses pulmonary artery smooth muscle cell proliferation in pulmonary hypertension (see whole document), and particularly that: “Pulmonary artery (PA) smooth muscle cell (SMC) proliferation in pulmonary hypertension (PH) may be linked to dysregulated mammalian target of rapamycin (mTOR) signaling. The mTOR pathway involves two independent complexes, mTORC1 and mTORC2, which phosphorylate S6 kinase (S6K) and serine/threonine kinase (Akt), respectively, and differ in their sensitivity to rapamycin. Here, we evaluated rapamycin-sensitive mTOR substrates and PA-SMC proliferation in rats with monocrotaline (MCT)-induced PH (MCT-PH). Compared with cells from control rats, cultured PA-SMCs from MCTPH rats exhibited increased growth responses to platelet-derived growth factor, serotonin (5-hydroxytryptophan), IL-1b, insulin-like growth factor-1, or fetal calf serum (FCS), with increases in phosphorylated (Ser-473)Akt, (Thr-308)Akt, glycogen synthase kinase (GSK)3, and S6K reflecting activated mTORC1 and mTORC2 signaling. Treatment with rapamycin (0.5 mM) or the Akt inhibitor, A-443654 (0.5 mM), reduced FCS-stimulated growth of PA-SMCs from MCT-PH rats to the level in control rats while inhibiting Akt, GSK3, and S6K activation. Neither the tyrosine kinase inhibitor, imatinib (0.1 mM), nor the 5-hydroxytryptophan transporter inhibitor, fluoxetine (5 mM), normalized the increased PA-SMC growth response to FCS. Rapamycin treatment (5 mg/kg/d) of MCT-PH rats from Day 21 to Day 28 markedly reduced phoshop (p)-Aky, p-GSK3, and p-S6K in PAs, and normalized growth of derived PA-SMCs. This effect was not observed after 1 week of imatinib (100 mg/kg/d) or fluoxetine (20 mg/kg/d). Rapamycin given preventively (Days 1–21) or curatively (Days 21–42) inhibited MCT-PH to a greater extent than did imatinib or fluoxetine. Experimental PH in rats is associated with a sustained proliferative PA-SMC phenotype linked to activation of both mTORC1 and mTORC2 signaling and is suppressed by rapamycin treatment.” (abstract).
Dou et al. teaches sustained delivery of rapamycin by subcutaneous injection of a cyclodextrin material-based nanocarrier (see whole document).
Dou et al. teaches that: “On the other hand, the nanomedicinal strategy has been proposed as a new approach for the management of cardiovascular disease by site specific cargo delivery for diagnosis and therapy. However, the development of efficient targeting nanomedicines for atherosclerosis with clinical significance is still challenging. First, due to the rapid clearance of intravenously (i.v.) injected nanoparticles by the mononuclear phagocyte system, their targeting efficiency to atherosclerotic lesions is low, even with delicate structure design and surface functionalization on therapeutic nanoparticles. Second, the retention time for nanomedicines accumulated in the plaque is too short from the view point of chronic diseases. To maintain the minimum effective concentration for a drug to achieve desirable efficacy, frequent dosing by i.v. administration is essential for targeted nanomedicines, which may be poorly acceptable by patients over a long period of time. Additionally, frequent administration may bring considerable economic and mental burden on patients' daily lives. This undesirable risk to benefit ratio makes the bench-to-bedside translation of currently developed nanotherapeutics extremely difficult with respect to antiatherosclerosis therapy. Taking these issues into account, sustained delivery systems that can release payload in a controlled manner over a long period of time are particularly desirable.” (p. 49, col. 1, first full paragraph).
Dou et al. teaches that: “Then we performed in vivo pharmacokinetic studies in mice after subcutaneous injection of Ac-bCD180-based RAP-NP (mean size, ~250 nm), which was employed for the following therapeutic studies. Consistent with the in vitro release behavior, in vivo pharmacokinetic study rendered a sustained profile of RAP concentration in the blood post subcutaneous administration of RAP-NP at 3 mg/kg of RAP (Fig. 2C). After an initial phase with relatively low concentration of RAP, nearly constant RAP levels (around 50 ng/L) were maintained for 13 days. […] These results suggested that in vivo release of RAP after subcutaneous administration was dominated by both passive diffusion and hydrolysis of nanocarriers.” (pp. 52-53, §3.3, 1st paragraph). And further that: “In RAP-NP groups, ApoE-/- mice were treated by subcutaneous administration every 15 days at the lower (1.0 mg/kg of RAP) and higher (3.0mg/kg of RAP) dose, respectively. Whereas treatment by the vehicle of blank Ac-bCD180 nanoparticles almost had no effect on the lesion area, RAP-NP significantly reduced the growth of atherosclerotic lesion (Fig. 3A).” (p. 54, col. 2). And further that: “After subcutaneous administration, RAP-NP can continuously release RAP at a constant rate for nearly 20 days.” (p. 60, col. 1, lines 5-7).
Finding of prima facie obviousness
Rationale and Motivation (MPEP 2142-2143)
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to treat pulmonary (arterial) hypertension using Nab-rapamycin by subcutaneous injection at a dose lower than 10 mg/m2 such as in the range of about 5 mg/m2 to about 10 mg/m2, as suggested by DESAI, specifically as per Houssaini et al. teaching that rapamycin reverses pulmonary artery smooth muscle cell proliferation in pulmonary hypertension, and further to provide a subcutaneous formulation for sustained delivery, as suggested by Dou et al., in order to provide for better patient compliance by requiring less frequent injections.
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103(a).
Response to Arguments:
Applicant's arguments filed 11/17/2025 have been fully considered but they are not persuasive.
Applicant argues that: “Desai broadly discusses dosing of nanoparticles comprising rapamycin for treating pulmonary hypertension, but does not demonstrate efficacy for any specific dosing in human patients. Desai discloses dosing ranges that differ by as much as 1000-fold, at frequencies ranging from as often as daily to as infrequently as in 12-month intervals. See paragraph [0073] of Desai. Such broad ranges in both doses and dosing frequency encompass a vastly large number of possible distinct dosing regimens without a specific pointer to the dosing regimen comprising about 1 mg/m2 to about 10 mg/m2 of rapamycin, as recited in the present claims for human individuals.” (p. 11, 4th paragraph). And that: “Desai broadly discusses embodiments comprising administration of a taxane (i.e., nab-paclitaxel), and does not demonstrate efficacy for the specific dosage regimen in which a nab-rapamycin composition is administered as a treatment that does not comprise administration of a taxane, as recited in the pending claims.” (p. 11, last paragraph). And further that: “However, reading Desai as a whole, one of skill in the art would not have a reasonable expectation of success in arriving at the claimed dosing regimen, wherein a 6MWD performance in a human individual is improved after treatment with the claimed nab rapamycin composition. At best, in Example 20, Desai teaches that six-minute walk testing will mg/m2 be performed on patients receiving nab-rapamycin at a dosage ranging from 30 to 100 mg/m2. This dosing range is much higher than the dosing regimen as recited in the pending claims. And more generally, Desai discusses compositions comprising rapamycin with an extremely broad range of dosages as high as 1080 mg/m2. See, e.g., paragraph [0071] of Desai The Examiner points to paragraph [0071] of Desai for disclosing "about 1 to about 5 mg/m2 about 5 to about 10 mg/m2" of rapamycin in the nanoparticle composition and paragraph [0073] for disclosing exemplary dosing frequencies.” (p. 12, 1st paragraph).
In response the examiner argues that it was known before the time of the claimed invention that the maximum tolerated dose of nab-rapamycin was 100 mg/m2 (instant Specification, p. 8, [0052], last 4 lines) and Gasper et al. (p. 702, col. 2, §Nab-Rapamycin). DESAI teaches that: “In some variations, the nanoparticle composition is administered over a period of at least one month, wherein the interval between each administration is no more than about a week, and wherein the dose of rapamycin or a derivative thereof and/or a taxane ( e.g., paclitaxel) at each administration is about 0.25% to about 25% of its maximum tolerated dose following a traditional dosing regime. […] about 1 % to about 20% of its maximum tolerated dose following a traditional dosing regime. In some variations, the dose of rapamycin or a derivative thereof per administration is less than about any of 25%, 24%, 23%, 22%, 20%, 18%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1 % of the maximum tolerated dose [MTD].” [emphasis added]([0089]). Therefore, the DESAI suggest a dose of nab-rapamycin of “about 0.25% to about 25% of its maximum tolerated dose” where 0.25 of 100 mg/m2 is 0.25 mg/m2 and 25% is 25 mg/m2, and 1% of the MTD is 1 mg/m2 and 10% of the MTD is 10 mg/m2. And while DESAI does disclose doses of up to 1080 mg/m2 ([0071]), one of ordinary skill in the art would have considered a much lower dose such as in the range of a fraction of the MTD, as discussed above.
In response to Applicants arguments regarding the 6MWD performance, the examiner argues that the prior art clearly does not have to suggest Applicants actual results to properly support a prima facie case of obviousness. "[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer." (MPEP §2112-I), “There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the relevant time, but only that the subject matter is in fact inherent in the prior art reference.” (MPEP §2112-II). MPEP §2112.02-II makes clear that: “The discovery of a new use for an old structure based on unknown properties of the structure might be patentable to the discoverer as a process of using. In re Hack, 245 F.2d 246, 248, 114 USPQ 161, 163 (CCPA 1957). However, when the claim recites using an old composition or structure and the "use" is directed to a result or property of that composition or structure, then the claim is anticipated. In re May, 574 F.2d 1082, 1090, 197 USPQ 601, 607 (CCPA 1978) (Claims 1 and 6, directed to a method of effecting nonaddictive analgesia (pain reduction) in animals, were found to be anticipated by the applied prior art which disclosed the same compounds, as well as a method of using them for effecting analgesia but which was silent as to addiction. The court upheld the rejection and stated that the inventors had merely found a new property of the compound and such a discovery did not constitute a new use. […] "While the references do not show a specific recognition of that result, its discovery by appellants is tantamount only to finding a property in the old composition." 363 F.2d at 934, 150 USPQ at 628 (emphasis in original)). “Mere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention.” (MPEP §2145(II)).
Applicant further argues that : “Applicant respectfully submits that the Examiner has not established a prima facie case of inherency in the allegation that the missing claim limitation of an improved 6MWD performance is inherently present in Desai. Per the standard for inherency set forth in Par Pharm, the Examiner has provided no rationale to support that a 6MWD performance in the individual of about 15% or higher is necessarily present or the natural result of the disclosure in Desai. As explained above, Desai does not teach or suggest the specific dosage regimen recited in the pending claims for treatment of human individuals with a nab-rapamycin composition without administration of a taxane. Further, an improved 6MWD performance was not observed in Desai, much less an improved 6MWD performance due to administration of the claimed nab rapamycin composition at a dose of about 1 mg/m2 to about 10 mg/m2. Even if one of skill in the art would have thought to alter the 30 mg/m2 to 100 mg/m2 dosage regimen of Example 20 with
the vague dosing range disclosure from paragraph [0071] of Desai, the Examiner has not explained why the claimed 6MWD performance improvement is necessarily present or the natural result.” (p. 13, 2nd paragraph).
In the instant case DESAI clearly does teach treating PAH (“Methods and compositions for treating pulmonary hypertension” – Title; and “In some variations, the pulmonary hypertension is pulmonary arterial hypertension (PAH). In some variations, the PAH is idiopathic PAH. In some variations, the PAH is familial PAH.” ([0011]). “The invention also provides a method of treating pulmonary hypertension in an individual by intravenous, intra-arterial, intramuscular, subcutaneous, inhalation, intraperitoneal, nasally, or intra-tracheal administering to the individual (e.g., a human) an effective amount of a composition comprising nanoparticles that comprise rapamycin or a derivative thereof and a carrier protein ( e.g., albumin such as human serum albumin).” ([0077]). “In some variations, the effective amount of rapamycin or a derivative thereof in the composition is included in any of the following ranges: about 1 to about 5 mg/m2 , about 5 to about 10 mg/m2 […].” ([0071]). Given that the patient class (PAH – human patients), the composition nab-rapamycin, the administration and the dose are the same as suggested by DESAI the results such as 6MWD would have been the same as well. Applicant further has argued unexpected results: “The present application as filed demonstrated that human patients with pulmonary arterial hypertension who were intravenously or subcutaneously administered with nab-rapamycin at a dose of about 1 mg/m2 to about 10 mg/m2, wherein the composition is administered about once a week, two out of three weeks, or three out of four weeks, showed surprising improvements in 6MWD. Part C of Example I of the present application showed that five patients completed sixteen weeks of treatment with once weekly intravenous administration of ABI-009 at a dose of 1 mg/m2 to about 10 mg/m2. Specifically, three patients were treated at a dose of 5-10 mg/m2 for sixteen weeks, and two patients were treated at a dose of 1 mg/m2 for sixteen weeks. All five patients demonstrated improvements in at least some of the functional capacity or hemodynamic endpoints, including an average of 34% improvement in 6MWD at 16 weeks. See, FIG. 3. Additionally, Part A of the Example I reports on a patient (subject #3) who was treated weekly with a dose of between 5mg/m2 and 10 mg/m2 of nab-sirolimus. The patient showed major improvement in 6MWD from 290 m to 397.5 m after only four weeks of treatment. After 16 weeks of treatment, the subject's 6MWD increased to 425 m.” (p. 10, 3rd paragraph)1. Applicant concludes that: “These data show that the claimed dosage regimen exerts significantly improved 6MWD while retaining the safety in view of Example 1, which shows the remarkable effect of the claimed method. These results would not have been predictable in view of the teaching of Desai, Houssaini, Dou, and Gasper, single or in combination. The advantageous property of the method recited in claim 1, as supported by the data presented in the application and Hou Declarations 1 and 2, provides strong evidence of non-obviousness.” (p. 11, 1st paragraph)1(instant Arguments, p. 9, last paragraph).
In response to Applicants allegation of unexpected results, the examiner argues that the DESAI reference clearly provides a basis for expecting that treating pulmonary arterial hypertension (PAH) in a human patient with nab-rapamycin would have been effective, particularly for the full scope of the disclosed ranges of doses which are described by DESAI as “effective amounts” ([0071]). MPEP §716.02(c)(II) “Expected beneficial results are evidence of obviousness of a claimed invention, just as unexpected results are evidence of unobviousness thereof.”
Although the record may establish evidence of secondary considerations which are indicia of nonobviousness, the record may also establish such a strong case of obviousness that the objective evidence of nonobviousness is not sufficient to outweigh the evidence of obviousness. Newell Cos. v. Kenney Mfg. Co., 864 F.2d 757, 769, 9 USPQ2d 1417, 1427 (Fed. Cir. 1988), cert. denied, 493 U.S. 814 (1989); Richardson-Vicks, Inc., v. The Upjohn Co., 122 F.3d 1476, 1484, 44 USPQ2d 1181, 1187 (Fed. Cir. 1997). Applicant is reminded that the submission of objective evidence of patentability does not mandate a conclusion of patentability in and of itself. In re Chupp, 816 F.2d 643, 2 USPQ2d 1437 (Fed. Cir. 1987).
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 1, 3-4, 6-7, 10, 15-16, 18, 20, 22, 24-25, 27-29, 33, 35-3, 40-41 and 43-46 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 2, 4-5 11, 13, 14-15, 23, 25 and 27, of copending Application No. 17/438,825 (hereafter ‘825 in view of DESAI (US 2010/0166869).
Instant claim 1 is discussed above.
Copending ‘825 claim 1 recites a method of treating a disease in an individual, comprising subcutaneously administering to the individual a pharmaceutical composition comprising nanoparticles comprising an mTOR inhibitor and an albumin, wherein the mTOR inhibitor in the pharmaceutical composition is at a dose of about 0.1 mg/m2 to about 10 mg/m2 for each administration. Copending ‘825 claim 27 limits the mTOR inhibitor to rapamycin.
The difference between the instantly rejected claims and the claims of copending ‘825 is that the claim of copending ‘825 do not expressly claim the disease condition is pulmonary (arterial) hypertension.
DESAI teaches methods for treating, stabilizing, preventing, and/or delaying pulmonary hypertension by administering nanoparticles that comprise rapamycin or a derivative thereof, and a protein carrier, as discussed above and incorporated herein by reference.
It would have been prima facie obvious before the effective filing date of the claimed invention that the instantly rejected claims are an obvious variant of the claims of copending ‘825 because the claims include the same administration method (subcutaneous) of the same composition (Nab-rapamycin) in the same dose. The skilled artisan would have been motivated to modify the claims of copending ‘825 and produce the instantly rejected claim because the treatment of pulmonary hypertension would have been beneficial for patients having this disease condition. Furthermore, the skilled artisan would have had a reasonable expectation of success in producing the invention of the instantly rejected claims because the copending claims include the same administration method (subcutaneous) of the same composition (Nab-rapamycin) in the same dose.
This is a provisional obviousness-type double patenting rejection.
Response to Arguments:
Applicant's arguments filed 05/14/2025 have been fully considered but they are not persuasive.
The examiner acknowledges applicant's wish to hold the foregoing provisional obvious-type double patenting rejection in abeyance until allowable subject matter is indicated. Applicant is advised that the Patent Office does not hold either objections or rejections in abeyance, therefore the rejection is maintained.
Applicant is reminded that the merits of a provisional obviousness-type double patenting rejection can be addressed by both the applicant and the examiner without waiting for the first patent to issue. In re Mott, 539 F.2d 1291, 190 USPQ 536 (CCPA 1976); In re Wetterau, 356 F.2d 556, 148 USPQ 499 (CCPA 1966).
Conclusion
Claims 1, 3-4, 6-7, 10, 15-16, 18, 20, 22, 24-25, 27-29, 33, 35-38, 40-41 and 43-46 are pending and have been examined on the merits. Claim 1, 3-4, 6-7, 10, 15-16, 18, 20, 22, 24-25, 27-29, 33, 35-38, 40-41 and 43-46 are rejected under 35 U.S.C. 103; and claims are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims of copending Application No. 17/438,825. No claims allowed at this time.
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 IVAN A GREENE whose telephone number is (571)270-5868. The examiner can normally be reached on M-F, 8-5 PM PST.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, David J. Blanchard can be reached at (571) 272-0827. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/IVAN A GREENE/Examiner, Art Unit 1619
/TIGABU KASSA/Primary Examiner, Art Unit 1619
1 Applicant arguments filed 05/14/2025.