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 Claims 31 and 32 have been withdrawn based upon Restriction/Election.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. The response filed 05/26/2026 included no claim amendments.
Request for Continued Examination
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 05/26/2026 has been entered.
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All rejections and/or objections not explicitly maintained in the instant office action have been withdrawn per Applicants’ claim amendments and/or persuasive arguments.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.
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 remain 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 05/26/2026 have been fully considered but they are not persuasive.
Applicant argues that: “None of Desai, Houssaini, Dou, or Gasper, alone or in combination, disclose a method of treating pulmonary arterial hypertension in a human individual, wherein the method comprises administering to the human individual a nab-rapamycin composition comprising nanoparticles comprising rapamycin and an albumin at a dose of about 1 mg/m2 to about 10 mg/m2, about once a week, two out of three weeks, or three out of four weeks, without administration of a taxane, and wherein administration of the composition produces a 6MWD performance in the individual of about 15% or higher after the treatment as compared to the 6MWD performance in the individual before administration of the composition, as recited in the pending claims.” (p. 8, 3rd paragraph). Applicant particularly argues that the claimed 6MWD performance result limitation is not inherently disclosed by DESAI (p. 8, item A). And “Applicant respectfully submits that the Examiner has not met the burden required for an obviousness rejection reliant on inherency. As stated in MPEP 2112, "In relying upon the theory of inherency, the examiner must provide a basis in fact and/or technical reasoning to reasonably support the determination that the allegedly inherent characteristic necessarily flows from the teachings of the applied prior art." […](emphasis in original). "The fact that a certain result or characteristic may occur or be present in the prior art is not sufficient to establish the inherency of that result or characteristic." […].” (p. 9, 3rd paragraph). Applicant takes the position that: “At best, in Example 20, Desai teaches that six-minute walk testing will be performed on patients receiving nab-rapamycin at a dosage ranging from 30 mg/m2 to 100 mg/m2-a dosing range that is 3-fold to 100-fold higher than the dose of about 1 mg/m2 to about 10 mg/m2 as recited in the pending claims.” (p. 10, 3rd paragraph). Applicant further argues that: “In Apotex, only 4-5% of the patients not achieving the claimed results was sufficient for the PTAB to find no inherent disclosure of the claimed results. In the instant application, 40% (2/5) of patients failed to achieve the claimed result in the study described in Example 1 (Part D) of the application. In the phase 1/1 b clinical study of ABI-009, 23% (3/13) of patients did not have an increase in 6MWD at all. Accordingly, the 15% or higher improvement in the 6MWD performance cannot be said to "naturally result" from administration of the composition to treat pulmonary arterial hypertension and is therefore not inherently disclosed.” (paragraph bridging pp. 11-12).
In response the examiner argues that the claimed method steps are clearly within the scope of the disclosure of DESAI which is directed to the exact same subject matter as the instant claims. One of ordinary skill would have clearly utilized the minimum amount of nab-rapamycin to achieve the desired results of treating pulmonary hypertension in order to minimize cost of the treatment. The claimed results necessarily result from the claimed method steps and therefore would have necessarily flowed from the same. The patient class is not different and therefore the results would not have been different. Particularly, 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 argues that “None of Desai, Houssaini, Dou, or Gasper, alone or in combination, disclose the claimed method” (p. 12, item B). And particularly that: “None of Desai, Houssaini, Dou, or Gasper, alone or in combination, disclose a method of treating pulmonary arterial hypertension with the specific dosage regimen of the nab-rapamycin composition as recited in the pending claims, wherein administration of the composition produces a 6MWD performance in the individual of about 15% or higher after the treatment as compared to the 6MWD performance in the individual before administration of the composition.” (p. 12, 2nd paragraph). Applicant further 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. 12, 3rd 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.” (paragraph bridging pp. 12-13). 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. 13, 2nd 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. Additionally, one of ordinary skill would have clearly utilized the minimum amount of nab-rapamycin to achieve the desired results of treating pulmonary hypertension in order to minimize cost of the treatment.
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. “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 unexpected results support non-obviousness (C), particularly that: “As further evidence of non-obviousness, Applicant has demonstrated that patients with pulmonary arterial hypertension who were intravenously administered nab-rapamycin at a dose of about 1 mg/m2 to about 10 mg/m2 showed surprising and clinically significant improvements in 6MWD. As discussed above, in Example 1 (Part D) of the application, three out of five patients who completed sixteen weeks of IV administration of ABI-009 showed a 16% to 47% increase in 6MWD, of which two improved more than 130 meters in 6MWD. The larger cohort phase 1/1 b clinical study of ABI-009 (ClinicalTrial.gov ID: NCT02587325) further showed that 6MWD was increased in 10 out of 13 (77%) patients, and was increased >60 meters in 5 out of 13 (38%) patients and> 130 meters in 2 out of 13 (15%) patients. See Hou Declaration 1 dated January 19, 2024, at ,¶ 18.” (p. 14, 1st paragraph). Applicant further argues that: “These results would not have been predictable from the teachings of Desai, Houssaini, Dou, and Gasper, alone or in combination. The cited references do not teach or suggest that the administration of the claimed rapamycin composition produces an improved 6MWD performance in the individual of about 15% or higher, as recited in amended claim 1.” (p. 14, 2nd 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 05/26/2026 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.
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.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/IVAN A GREENE/Examiner, Art Unit 1619
/TIGABU KASSA/Primary Examiner, Art Unit 1619
Prosecution Insights