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 .
Continued Examination Under 37 CFR 1.114
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 06/08/26 has been entered.
Receipt is acknowledged of Amendments, Remarks and an IDS filed on 06/08/26. Claims 1 and 12 have been amended and claims 16-18 have been canceled. No new claims have been added. Accordingly, claims 1, 3-5, 8-9, 12-14 and 19-29 remain pending and under examination on the merits.
Rejections and/or objections not reiterated from the previous Office Action are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set of rejections and/or objections presently being applied to the instant application.
Applicant’s claims
Claim 1 is broadest claim and is drawn to a method of modulating an immune response in a patient in need thereof, comprising administering by inhalation to the lungs of the patient an appropriate amount of a dry powder composition of drug particles comprising tacrolimus, the patient being administered a dose, wherein the dose comprises an amount of tacrolimus from about 1 mg, once per day during a 24 hour period for 3 consecutive days sufficient to generate a blood concentration of tacrolimus in the patient of 3 ng/mL to about 15 ng/mL at a time point of 24 hours after the administration once the patient has been administered the dose for 3 consecutive days, wherein the drug particles are formed using a thin film freezing process comprising dissolving tacrolimus and lactose monohydrate in a cosolvent mixture of acetonitrile and water, then freezing the solution by dropwise addition to the surface of a rotating drum cooled with liquid nitrogen, and collecting and drying the drug particles by lyophilization to remove acetonitrile and water.
Claim interpretation
Claims are directed to a method of modulating an immune response by administering by inhalation a dose of tacrolimus and wherein the dose is sufficient to generate a blood concentration of from 3 ng/mL to about 15 ng/mL at a time point of 24 hours after administration. The claim contains the critical step of administering by inhalation a sufficient amount of tacrolimus. The blood concentration however, is the results achieved after administration and is not a patentable limitation of the claimed method. Additionally, it is considered that the claimed method would necessarily achieve the same results as the results are the property of the formulation administered.
Accordingly, the below rejections meet the claimed method while not referencing the claimed blood concentration range.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1, 3-5, 8-9, 12-14 and 19-29 are rejected under 35 U.S.C. 103 as being unpatentable over Sahakijpijarn et al (Using thin film freezing to minimize excipients in inhalable tacrolimus dry powder formulations) in view of Dalby et al (WO 2011163600, cited in the IDS of 07/12/23 or its US version US 20110318277) (recitations are from the US document) and Watts et al (Characterization and pharmacokinetic analysis of tacrolimus dispersion for nebulization in a lung transplanted rodent model; cited in the IDS of 07/12/23, published 2010).
Sahakijpijarn et al teach high-potency tacrolimus dry powder for inhalation using thin film freezing (TFF) and that using ultra-rapid freezing can increase drug loading up to 95% while maintaining good aerosol performance. Drug loading affected the specific surface area and moisture sorption of TFF formulations, but it did not affect the chemical stability, physical stability, and dissolution of tacrolimus. Tacrolimus remained amorphous after storage at 40 °C/75% RH, and 25 °C/60% RH for up to 6 months. Lactose functioned as a bulking agent, and it had little to no effect as a stabilizer for amorphous tacrolimus due to a lack of interaction between the drug and excipient (See abstract).
It is disclosed that strategies to prevent or treat chronic graft rejection have not been successful. One such strategy is maintenance immunosuppressive therapy, which aims to prevent lung rejection by affecting multiple immune pathways. However, this strategy must manage the tradeoff between successful therapy and the long-term toxicities associated with immunosuppression (See paragraph bridging pages 1 and 2).
It is disclosed that “Watts et al. used TFF to develop a DPI tacrolimus formulation containing 50% tacrolimus and 50% lactose (Watts et al., 2013). Amorphous tacrolimus prepared using TFF showed an improvement in both sink and non-sink dissolution profiles in simulated lung fluid (Sinswat et al., 2008)”. And that the TFF aims to use thin film freezing to develop dry powder inhalation formulations (DPIs) containing a high drug loading of tacrolimus (See page 3, 1st col, 1st full and last paragraphs).
The aerodynamic properties of TFF powder were evaluated using a Plastiape® RS01 inhaler containing size-3 HPMC capsules and approximately 3–6 mg of formulation (See section 2.5 and 2.13).
It is also disclosed that TFF powder (1–3 mg) was loaded into a 70 μL alumina crucible with a pierced covering to reduce static evaporation (See section 2.9). and that TFF powder of F6 (about 3.1–3.3 mg) was filled into a size-3 HPMC capsule (See section 2.14).
Sahakijpijarn et al, in Table 4, discloses summary of the physical and aerodynamic properties of tacrolimus dry powder formulations prepared using TFF. The table discloses MMAD ranges of from 2.41 to 3.4 µm and GSD ranges of from 2.6 to 3.24 µm for tacrolimus particles.
Sahakijpijarn et al teach that for 50–95% drug loading, the MMADs and FPFs were in the range of 2.0–2.6 μm and 61–71%, respectively. When drug loading was increased to 100%, F6 exhibited the highest MMAD (3.58 ± 0.36 μm) and the lowest FPF (54.21 ± 3.90%). The effect of the excipient on aerosol performance was also observed. At 95% drug loading, F6 showed a lower MMAD and a higher FPF than F8 and F9 (p < 0.05), which indicates that lactose is better than mannitol and trehalose in terms of aerosol performance (See section 3.2).
Sahakijpijarn et al conclude that dry powders of tacrolimus for inhalation produced using TFF would be a promising alternative therapy for the treatment of patients with lung transplantation rejection (See section 5. Conclusion).
Regarding the preparation process, Sahakijpijarn et al teach that tacrolimus and excipients (e.g., lactose monhydrate, mannitol, trehalose) were dissolved in a mixture of acetonitrile and water (60:40 v/v). The solids content in the solvent mixture was prepared at 0.75% w/v or 2.5% w/v. The solution was passed through a 0.45 μm PVDE syringe filter and dropped from a height of 10 cm onto a rotating cryogenically cooled stainless-steel drum. The frozen samples were collected in a stainless-steel container filled with liquid nitrogen and then transferred into a −80 °C freezer before drying in a lyophilizer (See Page, sections 2.1 and 2.2).
While Sahakijpijarn et al disclose loading from 1 to 3 mg of the formulation in a capsule for inhalation and disclose that the ratio of tacrolimus to lactose is preferably 1:1 (50% of each), they do not expressly disclose the a once daily dosing or blood concentrations. These are however known in the art and would have been obvious to one of ordinary skill in the art as shown by Dalby et al and Watts et al.
Dalby et al teach a highly concentrated solution-based formulation of tacrolimus, along with related methods of administration and treatment (See abstract and [0007]). The concentration of tacrolimus ranges from 0.16 to about 2.5 weight percent (% w/w) (See [0014]).
Dalby et al disclose a method of treating or preventing lung transplant rejection in a subject, e.g., a human subject, the method comprising administering by inhalation a total daily metered dosage amount of from about 1 mg to about 10 mg of tacrolimus (e.g., 1, 2, 3, … mg), wherein the daily metered dosage amount is administered in once daily doses (See [0032]). Each of the doses consists of a single actuation event (See [0033]).
It is further stated that a therapeutically effective amount of tacrolimus for an adult will range from a total daily metered dosage of about 1 mg/day to about 10 mg/day, administered as a single daily dosage. In one particular embodiment, the regimen consists of two puffs per dose, once daily, or one puff per dose, once daily (i.e., a single administration event) (See [0106]).
Dalby et al also disclose that ““Pharmacologically effective amount” is the amount of an active agent present in an aerosolizable composition, needed to provide a desired level of active agent in the bloodstream or at the site of action (e.g., the lungs) of a subject to be treated to provide an anticipated physiological, biophysical, biochemical, or pharmacological response when such composition is administered pulmonarily. The precise amount will depend upon numerous factors, ….. and can readily be determined by one skilled in the art, based upon the information provided herein” (See [0056]).
Watts et al teach a variety of new pharmacotherapeutic strategies for prevention of lung allograft rejection. They disclose that direct administration of immunosuppressive agents to the lung is a commonly investigated approach. Characterization of the nebulized tacrolimus dispersion for nebulization showed a fine particle fraction (FPF) of 46.1% and a mass median aerodynamic diameter (MMAD) of 4.06 μm. After single dose administration to transplanted and non-transplanted rats, a mean peak transplanted lung concentration of 399.8 ± 29.2 ng/g and mean peak blood concentration of 4.88 ± 1.6 ng/mL were achieved. It is theorized that enhanced lung retention of tacrolimus is due to lipophilic associations with bronchial tissue and phospholipid surfactants in lung fluid. These findings indicate that tacrolimus dispersion for nebulization can achieve highly localized therapy for lung transplant recipients (See abstract and page 49, 2nd col.).
It would have been obvious to one of ordinary skill in the art at the time of invention to have combined the teachings of Dalby et al and Watts et al with that of Sahakijpijarn et al to arrive at the claimed invention with a reasonable expectation of success. It would have been obvious to do so because Sahakijpijarn et al teach a dry powder formulation comprising tacrolimus and lactose administered to a patient to increase long-term survival of a lung transplant patient. Sahakijpijarn et al teach the critical characteristics of the said dry powder formulation prepared by the thin film freezing process and including the dosage amounts of tacrolimus, the particles being amorphous, ratio of tacrolimus to sugar, MMAD and GSD of the particles. Dalby et al disclose the dosing of tacrolimus for patients wherein the suitable amount may be administered to achieve highest efficiency and lowest side effects and disclose that once daily dosing has been envisioned, tested and disclosed. Watts et al also teach inhalation method of tacrolimus after a single dose achieved a blood concentration of about 4 ng/mL and that the method is very effective in reducing or preventing organ rejection in a transplant patient. Accordingly, one of ordinary skill in the art given the teachings of Sahakijpijarn et al would have been motivated to look in the art for suggestions on the best dosage frequency as taught by Dalby et al and Watts et al with a reasonable expectation of success.
In other words, the claims would have been obvious because the technique for improving a particular formulation was part of the ordinary capabilities of a person of ordinary skill in the art, in view of the teaching of the technique for improvement in other situations.
Additionally, with regard to the concentration ranges (i.e. dosage amount), the courts have held that “Where 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, 105 USPQ 233 (CCPA 1955).
Claims 1, 3-5, 8-9, 12-14 and 19-29 are rejected under 35 U.S.C. 103 as being unpatentable over Sinswat et al (Nebulization of nanoparticulate amorphous or crystalline tacrolimus- Single-dose pharmacokinetics study in mice) in combination with Johnston et al (10,092,512), Dalby et al (WO 2011163600, cited in the IDS of 07/12/23 or its US version US 20110318277) (recitations are from the US document) and Watts et al (Characterization and pharmacokinetic analysis of tacrolimus dispersion for nebulization in a lung transplanted rodent model; cited in the IDS of 07/12/23, published 2010).
Sinswat et al teach developing a pulmonary composition of tacrolimus (TAC) providing direct access to the graft in lung transplant offering the possibility of high drug levels. The objective of this study was to investigate the physicochemical and pharmacokinetic characteristics of the nanostructured aggregates containing amorphous or crystalline nanoparticles of TAC produced by ultra-rapid freezing (URF). TAC and lactose (1:1 ratio) were investigated for pulmonary delivery (See abstract).
In dissolution testing, it is disclosed that powder samples (0.4 mg of TAC) equivalent to approximately 59% of the equilibrium solubility (6.8 μg/mL) were added to 100 mL of the modified simulated lung fluids (SLF) (See 2.3.4).
Sinswat et al teach the physicochemical properties of TAC powders produced by URF investigated and compared to the unprocessed TAC. The XRD pattern of URF-TAC:LAC confirmed that this composition was amorphous. This suggests that lactose inhibited crystallization of TAC. It is well known that sugars such as lactose can be used to stabilize amorphous drugs. The addition of sugars has been shown to extend the shelf life of amorphous systems by preventing crystallization. In addition, lactose is generally regarded as safe (GRAS) for use as an excipient in inhalation systems.
Comparison of the data suggests similar aerodynamic properties of the drug particles aerosolized from the two URF formulations. The MMAD was 2.57 and 2.86 μm for URF-TAC:LAC and URF-TAC, respectively, and the GSD was less than 2.2 (See Table 1 and 3.1).
Johnston et al teach dispensing of poorly water soluble compositions and/or protein via pMDI, sub-micron particles for drug delivery because smaller particles provide a larger surface area/mass ratio for dissolution. Johnston et al provides a unit-dose delivery system used as a template for use in a dry powder inhaler (See Summary).
It is disclosed that TFF technology was employed for the production of dry powders. Briefly, a cosolvent mixture of acetonitrile (ACN) and water was used to dissolve tacrolimus and sugar excipient. Tacrolimus and lactose (TACLAC), tacrolimus and mannitol (TACMAN), were dissolved in the cosolvent solution. The ratio of tacrolimus to excipient was 1 to 1 and each solution prepared for TFF had a total solids concentration of 0.75% w/v. All frozen blisters were lyophilized (See Col. 30, lines 56-67).
In Table 2, Johnston et al disclose the MMAD and GSD values for the inhaled particles.
Dalby et al and Watt et al’s teachings are delineated above and incorporated herein.
It would have been obvious to one of ordinary skill in the art at the time of invention to have combined the teachings of Johnston et al, Dalby et al and Watts et al with that of Sinswat et al to arrive at the claimed invention with a reasonable expectation of success. It would have been obvious to do so because Sinswat et al teach preparing a dry powder formulation comprising tacrolimus and lactose suspended in a solution and nebulized by a lung transplant patient. Sinswat et al teach the critical characteristics of the said dry powder formulation including the particles being amorphous, ratio of tacrolimus to sugar, MMAD and GSD of the particles. However, Sinsawat et al do not administer the formulation as dry powder. Johnston et al teach formulations of tacrolimus and lactose prepared as both dry powder and suspension for inhalation to a patient in need of an immune response after transplantation. The powders are made by TFF process. Dalby et al disclose the dosing of tacrolimus for patients wherein the suitable amount may be administered to achieve highest efficiency and lowest side effects and disclose that once daily dosing has been envisioned, tested and disclosed. Watts et al also teach inhalation method of tacrolimus after a single dose achieved a blood concentration of about 4 ng/mL and that the method is very effective in reducing or preventing organ rejection in a transplant patient. Accordingly, one of ordinary skill in the art given the teachings of Sinswat et al would have been motivated to look in the art for suggestions on the powder formulations for inhalation and best dosage frequency as taught by Johnson et al and Dalby et al and Watts et al with a reasonable expectation of success.
In other words, the claims would have been obvious because the technique for improving a particular formulation was part of the ordinary capabilities of a person of ordinary skill in the art, in view of the teaching of the technique for improvement in other situations.
Additionally, with regard to the concentration ranges (i.e. dosage amount), the courts have held that “Where 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, 105 USPQ 233 (CCPA 1955).
Response to Arguments
Applicant's arguments filed 06/08/26 have been fully considered but they are not persuasive.
Applicant states that “The inventors have surprisingly found that administering a dose of about 1.0 mg once per day during a 24-hour period for 3 consecutive days generates a blood concentration of tacrolimus in the patient of 3 ng/mL to about 15 ng/mL at a time point of 24 hours after the administration once the patient has been administered the dose for 3 consecutive days sufficient to prevent or slow rejection of a transplanted organ such as rejection of a transplanted kidney, heart, liver, or lung” (See Remarks, pages 7-8).
The statement/ comment is not sufficient to overcome the rejections. As shown above, Shakjipijarn et al teach the same method of making the same particles for inhalation. Dalby et al and Watts et al teach that a method of reducing the risk or preventing organ rejection in a transplant patient by inhalation of a formulation comprising tacrolimus to a subject in need thereof and wherein the dosage comprises from 1 mg of tacrolimus and is administered once a day and wherein the blood concentration after a single dose is about 4 ng/mL. Thus, the references meet each and every element of the claims, including the method making the dry powder composition. The same particles administered via the same method/route to the same subject would be expected to result in the same outcome, i.e. blood concentration. However, as disclosed by Watts et al, the same formulation administered to the same patient has resulted in the same blood concentration. Additionally, Shakjipijarn et al disclose that the said method of making the particles, provides the subject with increased systemic concentration over prolonged periods. It is disclosed that “local immunosuppression therapy with inhaled tacrolimus showed better clinical outcomes for preventing lung graft rejection with fewer side effects” (See entire document, especially page 2, 1st col, 2nd para).
Applicant further argues that “As illustrated in the Figures the claimed formulations result in a sufficient blood concentration over a 24-hour period that a patient only needs to be administered a dose once. Reducing the number of doses results in reduced side effects, reduced adverse events, and increased patient compliance” (See remarks, page 8).
This argument is also unpersuasive because as shown and stated above, the references do teach a once a day administration of tacrolimus by inhalation which results in the desired blood levels and as stated by the references reduces undesired side effects.
Further argued is that “As set forth in the specification at paragraph [0230], data from healthy volunteers (FIG. 1) from the 1 mg BID repeat dose group generally were predicted from the oral PK model with 75% F (absorption) that was developed to simulate systemic exposure of tacrolimus after pulmonary inhalation. See FIGS. 2A & 2B. The actual arithmetic mean of 45 ng/mL was in agreement with the simulated geometric mean exposure of slightly greater than 45 ng/mL. Actual trough values at 12 hours post dose on Day 1 and Day 7 were closer to the upper 90% confidence interval for simulated exposure. This preliminary pharmacokinetic data suggests that it is feasible to deliver low mg doses of tacrolimus by inhalation and achieve similar concentration values at trough within the TDM concentration range of 10-15 ng/mL at a lower total daily dose” (See Remarks, page 9).
This argument is similarly unpersuasive because as stated above, the prior art teaches the said method and formulation and the result achieved. Thus, the claimed method is properly rendered obvious by the teachings of the prior art.
Furthermore, as stated in the last Office Action, Fig. 9 of Sinswat actually shows that the concentration of tacrolimus in the blood is around 3-5 ng/ml at about 24 hours, which meets the claimed range. While the disclosure states “decreased rapidly”, this is a relative term and is comparing the levels at the 24 hours to levels at 3-4 hours which are at their highest. See below.
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As can be seen at 24 hours the line relating to TAC whole blood concentration does not line over the baseline (i.e. 0) but is more like 3-5 ng/mL. It is also noted that the above data is produced after a single inhalation, i.e. a once daily dosing is both envisioned and tested and shows that sufficient concentration of tacrolimus is present in the blood 24 hours after inhalation.
Furthermore, Sinswat et al disclose that: The levels of TAC decreased rapidly for URF-TAC:LAC with the last time point with detectable levels occurring at 24 h, while URF-TAC declined in a similar but slower manner (no significant difference in the Kel values (p > 0.05)). Whole blood concentrations of TAC were below the limit of quantification for both formulations at 48 hours. (See Page 1064). The recitation here and Fig. 9 show that at 24 hour point the concentration of tacrolimus in blood is about 3-5 ng/mL as claimed.
Additionally, Dalby et al teach the dose and once a day doing of an inhalable dry powder comprising tacrolimus and lactose.
It is further noted that claim 1 recites a dose of from 1 mg once per day, which encompasses nay dose from 1 mg and more.
Therefore, 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 at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Claims 1, 3-5, 8-9, 12-14 and 19-29 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Mina Haghighatian whose telephone number is (571)272-0615. The examiner can normally be reached M-F, 7-5 EST.
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/Mina Haghighatian/
Mina Haghighatian
Primary Examiner
Art Unit 1616
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