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 .
Receipt is acknowledged of Remarks filed on 06/18/25. No claims have been amended, added or canceled. Accordingly, claims 1, 3-9 and 11-12 remain under examination on the merits.
Information Disclosure Statement
The foreign documents listed on the IDS have not been provided in English, only English abstract has been provided.
Full English translation of CN 989953 and CN 101214227 have been attached. The recitations in the below rejections are from these documents.
NOTE: An English translation of the International Search Report has not been provided.
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.
Applicant’s claims Claim 1 is directed to a compound dry powder inhalant for treating idiopathic pulmonary fibrosis, consisting of baicalin, ambroxol hydrochloride, L-leucine and phosphate, wherein based on a mass of the compound dry powder inhalant, L-leucine accounts for 10-40%, phosphate accounts for 15-35%, and a total mass of baicalin and ambroxol hydrochloride accounts for 40-60%, and wherein a mass ratio of baicalin to ambroxol hydrochloride is 1:0.2 to 2; and the compound dry powder inhalant has a Dv90≤5 μm.
Claims 11-12 are directed to a method of treating idiopathic pulmonary fibrosis.
Claim interpretation:
Claims 8-9 are product-by-process claims. Product-by-process claims are examined on the limitations of the product. MPEP 2113, citing In re Thorpe, 111 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985) states that “[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process”.
Claims 1, 3-6, 8-9 are rejected under 35 U.S.C. 103 as being unpatentable over Wu et al (US 20200009334) in view of CN 1989953 and Lipp et al (US 20130213398).
Wu et al teach a preparation for inhalation use in form of dry powder comprising particles of ambroxol hydrochlorides, and at least a pharmaceutically acceptable excipient and/or dispersant, which constitutes a composition for inhalation use with optimum performances which, combined with inhaler action, reaches and acts directly on the bronchi or on the damaged respiratory tract (See abstract).
It is disclosed that the said composition may comprise from 20 to 59% of ambroxol hydrochloride and 41 to 80% of one or more excipient. The one or more excipients include leucine (See [0029]-[0030] and claims 1-5).
The particles have a fine particle size, i.e. diameter of from 3-5 µm (See [0032], [0049] and [0052]). The fine particle fraction (FPF) deposit rate of this product is 0-50% (See [0061]).
Wu et al also disclose that the said powders are prepared by spray drying (See [0013], [0041] and [0049]).
Wu et al lack a disclosure on adding baicalin, phosphate or their amounts. The modifications would have been obvious in view of the prior art’s disclosure including CN ‘953 and Lipp et al.
CN ‘953 teach a composition comprising ambroxol and baicalin to treat respiratory conditions (See abstract). The said ambroxol is preferably in the hydrochloride salt (See Page 3, lines 9-10)
The said compositions may be in the form of a powder and administered via inhalation (See page 3, 7th para). Suitable excipients include calcium phosphate (See page 3, 8th para).
Disclosed are pharmaceutical compositions, comprising in parts by weight: 5-120 parts of ambroxol or its pharmaceutically acceptable salts, 125-2000 parts of baicalin, reading on a ratio of baicalin to ambroxol 1:02-2.
Lipp et al teach respirable dry particles for delivery of divalent metal cation salts and/or monovalent cation salts to the respiratory tract and methods for treating a subject having a respiratory disease and/or infection (See abstract).
Disclosed is a respirable dry powder comprising respirable dry particles comprising a magnesium salt, one or more therapeutic agents, and optionally an excipient. The said magnesium salt may be magnesium phosphate (See [0012], [0100], claim 1 and [0103]).
Lipp et al disclose that the said respirable dry particles have a volume median geometric diameter (VMGD) of about 10 microns or less; a Fine Particle Fraction (FPF) of less than 3.4 microns of at least 30%, a mass median aerodynamic diameter (MMAD) of about 7 microns or less (See [0012]-[0013]). The said respirable dry powder is comprised of respirable dry particles with an MMAD between 1 to 4 µm or 1 to 3 µm (See [0287]). The said powders may have a Dv(50) of 3 µm or less (See Table 12).
The said powders may have about 5% to about 45% excipient, about 20% to about 90% magnesium salt, and about 0.01% to about 20% therapeutic agent (See [0014] and claim 55]). An example excipient is leucine. For example, the said respirable dry particles can contain the amino acid leucine, i.e. L-leucine in an amount of about 5% to about 30% by weight (See [0013], [0141]-[0142] and [0305]).
It would have been prima facie obvious to a person of ordinary skilled in the art at the time the invention was made to have combined the teachings of CN ‘953 and Lipp et al with that of Wu et al to arrive at the instant invention. It would have been obvious to do so because Wu et al teach a dry powder for inhalation comprising ambroxol hydrochloride and suitable excipients for delivery into the pulmonary system. CN 953 also teaches a dry powder composition comprising a mixture of ambroxol and baicalin for delivery by inhalation. Lipp et al is also drawn to a dry powder composition for effective inhalation and delivery of one or more active agents into the pulmonary system for treatment. Lipp et al disclose that a dry powder composition comprises one or more active agents, a metal salt and leucine and provide guidance on their amounts. Lipp et al further disclose specifics of an effective dry powder for inhalation including MMAD, particle size distribution, FPF, etc. Thus, one of ordinary skill in the art having possession of the said teachings would been motivated to have combined the disclosures and prepared a dry powder composition comprising both baicalin and ambroxol hydrochloride, leucine and phosphate at the suggested particle size and FPF values with a reasonable expectation of success.
In other words, all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would have yielded predictable results to one of ordinary skill in the art at the time of the invention.
The claims would have been obvious because a person of ordinary skill has good reasons to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense. For example, it would have been obvious to one of ordinary skill in the art to have incorporated CN ‘953’s guidance and included baicalin in the dry powder compositions of Wu et al because they are both effective active agents for treating respiratory conditions. By combining therapeutic agents in the same composition, the patient needs to take less medicaments which increases patient’s compliance.
From the combined teaching of the cited references, 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.
Claims 1, 3-9 are rejected under 35 U.S.C. 103 as being unpatentable over CN 101214227 in view of CN 1989953, Lipp et al (US 20130213398) and Caponetti (US 20160045434).
CN ‘227 teach an ambroxol hydrochloride dry powder inhaler and a preparation method thereof. The ambroxol hydrochloride inhalation is composed of ambroxol hydrochloride, dispersing glidant and diluent, and its percentage by weight is: 60%-90% of ambroxol hydrochloride, 10%-30% of dispersing glidant. The said powder is prepared by spray drying ambroxol hydrochloride or ambroxol hydrochloride and dispersing glidant to obtain powder, collect in gelatin or plastic capsules or aluminum contained in plastic blisters or in reservoir form within a multidose dry powder inhaler device. The said dry powder inhalation agent comprising ambroxol hydrochloride is directly inhaled into the respiratory tract and lungs through the drug delivery device, so that it can directly play a role in the respiratory tract, so as to achieve the purpose of safe, targeted, quick-acting and efficient treatment (See abstract).
It is disclosed that the said ambroxol hydrochloride dry powder inhalation is the spray-dried powder of ambroxol hydrochloride and glidant with a particle size of 1-5 μm, and put it in the form of a single dose of 15-30mg. The said glidant (fluidizer) is one or more of amino acids leucine, isoleucine, etc, (See page 2, 3rd and 5th para).
CN ‘227 also discloses that it is generally considered that particles with aerodynamic diameter, (Da) in the range of 1-5 μm are suitable for pulmonary administration (See page, 4, 3rd and 4th para).
CN ‘227 lack a disclosure on the baicalin, phosphate, their amounts and the moisture content. These are well known in the art and would have been obvious to incorporate especially in view of CN ‘953, Lipp et al and Caponetti et al.
CN ‘953 teach a composition comprising ambroxol and baicalin to treat respiratory conditions (See abstract). The said ambroxol is preferably in the hydrochloride salt (See Page 3, lines 9-10)
The said compositions may be in the form of a powder and administered via inhalation (See page 3, 7th para). Suitable excipients include calcium phosphate (See page 3, 8th para).
Disclosed are pharmaceutical compositions, comprising in parts by weight: 5-120 parts of ambroxol or its pharmaceutically acceptable salts, 125-2000 parts of baicalin, reading on a ratio of baicalin to ambroxol 1:02-2.
Lipp et al teach respirable dry particles for delivery of divalent metal cation salts and/or monovalent cation salts to the respiratory tract and methods for treating a subject having a respiratory disease and/or infection (See abstract).
Disclosed is a respirable dry powder comprising respirable dry particles comprising a magnesium salt, one or more therapeutic agents, and optionally an excipient. The said magnesium salt may be magnesium phosphate (See [0012], [0100], claim 1 and [0103]).
Lapp et al disclose that the said respirable dry particles have a volume median geometric diameter (VMGD) of about 10 microns or less; a Fine Particle Fraction (FPF) of less than 3.4 microns of at least 30%, a mass median aerodynamic diameter (MMAD) of about 7 microns or less (See [0012]-[0013]). The said respirable dry powder is comprised of respirable dry particles with an MMAD between 1 to 4 µm or 1 to 3 µm (See [0287]). The said powders may have a Dv(50) of 3 µm or less (See Table 12).
The said powders may have about 5% to about 45% excipient, about 20% to about 90% magnesium salt, and about 0.01% to about 20% therapeutic agent (See [0014] and claim 55]). An example excipient is leucine. For example, the said respirable dry particles can contain the amino acid leucine, i.e. L-leucine in an amount of about 5% to about 30% by weight (See [0013], [0141]-[0142] and [0305]).
Caponetti et al teach inhalation formulations of drugs in the form of dry powder for inhalation administration deliverable as such with an inhaler and provided with high deliverability, respirability and stability (See abstract).
Caponetti et al disclose a pharmaceutical composition for inhalation in powder form, comprising an active principle in an amount greater than 1% by weight and leucine in amount from 5 to 70% by weight (See [0046] and claim 1).
It is also disclosed that the preferred particle size for this powder provides that at least 50% of the size distribution (X50) is below 5 μm, preferably below 3 μm, more preferably below 2.0 μm, also to increase the surface area optimizing deep lung deposition. A powder with a moisture content of less than 10%, preferably less than 5%, more preferably below 3%. The amount of moisture present in the composition is controlled by the presence of leucine, which limits the content due to its hydrophic features (See [0081]-[0082]).
It would have been prima facie obvious to a person of ordinary skilled in the art at the time the invention was made to have combined the teachings of CN ‘953, Lipp et al and Caponetti et al with that of CN ‘227 to arrive at the instant invention. It would have been obvious to do so because CN ‘227 teach a dry powder for inhalation comprising ambroxol hydrochloride and suitable excipients including leucine for delivery into the pulmonary system. CN 953 also teaches a dry powder composition comprising a mixture of ambroxol and baicalin for delivery by inhalation. Lipp et al is also drawn to a dry powder composition for effective inhalation and delivery of one or more active agents into the pulmonary system for treatment. Lipp et al disclose that a dry powder composition comprises one or more active agents, a metal salt and leucine and provide guidance on their amounts. Lipp et al further disclose specifics of an effective dry powder for inhalation including MMAD, particle size distribution, FPF, etc. Thus, one of ordinary skill in the art having possession of the said teachings would been motivated to have combined the disclosures and prepared a dry powder composition comprising both baicalin and ambroxol hydrochloride, leucine and phosphate at the suggested particle size and FPF values with a reasonable expectation of success. Additionally, Caponetti et al teach another dry powder composition comprising one or more active agents and leucine for delivery by inhalation and disclose that the moisture content of the said dry powder is less than 5% and that leucine effectively controls this moisture content.
In other words, all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would have yielded predictable results to one of ordinary skill in the art at the time of the invention.
The claims would have been obvious because a person of ordinary skill has good reasons to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense. For example, it would have been obvious to one of ordinary skill in the art to have incorporated CN ‘953’s guidance and included baicalin in the dry powder compositions of CN ‘227 because they are both effective active agents for treating respiratory conditions. By combining therapeutic agents in the same composition, the patient needs to take less medicaments which increases patient’s compliance.
From the combined teaching of the cited references, 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.
Claims 1 and 11-12 are rejected under 35 U.S.C. 103 as being unpatentable over Wu et al (US 20200009334) in view of CN 1989953, Lipp et al (US 20130213398), P. R. Gupta (Ambroxol hydrochloride in the management of idiopathic pulmonary fibrosis: clinical trials are the need of the hour) and Zhao et al (Baicalin alleviates bleomycin-induced pulmonary fibrosis proliferation in rats via the PI3K/AKT signaling pathway).
The teachings of Wu et al, CN ‘953 and Lipp et al are delineated above and incorporated herein.
The references disclose dry powder compositions comprising ambroxol hydrochloride, baicalin, leucine and phosphate for inhalation into the subject’s lung for treating respiratory conditions. However, there is no express disclosure for treating idiopathic pulmonary fibrosis. This is taught in the art by Gupta and Zhao et al.
P. R. Gupta teach, in this clinical trial report that idiopathic pulmonary fibrosis (IFP) has been successfully treated by ambroxol hydrochloride. It is disclosed that ambroxol hydrochloride has anti-inflammatory and anti-oxidant properties. “Ambroxol may have the potential to check the dysregulated healing process that is typical of IPF. This, coupled with its safety profile for human use, warrants clinical trials of the drug in the management of IPF” (See abstract).
It is disclosed that “it is being hypothesized that ambroxol has the potential to check the process of epithelial mesenchymal transition, mediated chiefly by cytokine TGF-β1 as shown in [Figure 1] and thereby to check the typical dysregulated healing process of IPF (See page 46, 3rd para).
Zhao et al also teach that baicalin is an important flavonoid compound that is isolated from the Scutellaria baicalensis Georgi Chinese herb and plays a critical role in anti-oxidative, anti-inflammatory, anti-infection and anti-tumor functions. Collectively, the results of the present study suggested that baicalin exerted a suppressive effect on BLM-induced pulmonary fibrosis and fibroblast proliferation (See abstract).
It is disclosed that “baicalin also inhibited BLM-induced pulmonary fibrosis by upregulating adenosine A2a receptor and downregulating transforming growth factor (TGF)-β1 and phosphorylated (p)-ERK1/2 expression. These results indicate that baicalin is a potential treatment for IPF. Thus, it is of great significance to investigate the specific mechanism and signaling pathway via which baicalin inhibits pulmonary fibrosis, as this may be a theoretical basis for the use of baicalin in the treatment of IPF” (See page 2322, 1st col. 2nd para).
Zhao et al disclose that “In conclusion, the present study suggested that baicalin inhibited histopathological damage and lung fibroblast proliferation in BLM-induced pulmonary fibrosis, and that this effect was at least in part, mediated via the CaMKII and PI3K/AKT signaling pathways. The present results provide novel insights into the protective effects of baicalin in pulmonary fibrosis and the underlying mechanisms, which may become the theoretical basis for the use of baicalin in the management of IPF” (See paragraph bridging pages 2331-2332).
It would have been prima facie obvious to a person of ordinary skilled in the art at the time the invention was made to have combined the teachings of CN ‘953, Lipp et al, Gupta and Zhao et al with that of Wu et al to arrive at the instant invention. The reason for combining CN ‘953 and Lipp et al with Wu et al is delineated above and incorporated herein.
Additionally, one of ordinary skill in the art would have been motivated to have used the dry powder of the combined references for treating IPF because Gupta teaches that ambroxol hydrochloride has anti-oxidative and anti-inflammatory properties and is effective in treating IPF. Similarly, Zhao et al teach that baicalin has anti-oxidative and anti-inflammatory effects and is successful in treating IPF. That is by following the teachings of the prior art, one of ordinary skill in the art is led to the claimed method of treating IPF and claimed dry powder.
In other words, all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would have yielded predictable results to one of ordinary skill in the art at the time of the invention.
From the combined teaching of the cited references, 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.
Response to Arguments
Applicant's arguments filed 06/18/25 have been fully considered but they are not persuasive.
Applicants’ main argument is that they have discovered superior results in the claimed combination in treating idiopathic pulmonary fibrosis (IPF).
Specifically, Applicants argue that “Applicant has for the first time discovered that the drug combination of baicalin (BA) and ambroxol hydrochloride (AH) exhibits significant synergistic effects in the treatment of the specific disease idiopathic pulmonary fibrosis (IPF), with the efficacy being notably higher than the simple additive effect of monotherapy of BA or AH. Specifically, pharmacodynamic studies in the specification demonstrate that the combination of baicalin (BA) and ambroxol hydrochloride (AH) in the compound dry powder inhalant (DPI) has superior therapeutic effects compared to BA or AH alone, supported by multiple experimental datasets that highlight their synergistic effects” (See Remarks, pages 2-3).
The above argument is not sufficient to overcome the rejections. With regard to claims 1 and 3-9, as stated above, the claims are drawn to a compound dry powder inhalant consisting of baicalin, ambroxol hydrochloride, L-leucine and phosphate at recited concentration ranges. The limitation of “for treating idiopathic pulmonary fibrosis” is an intended use limitation and does not materially affect the scope of the dry powder. Also, claims 8-9 are product-by-process claims in which the process is not given patentable weight as the claims are drawn to the product. That is, Product-by-process claims are examined on the limitations of the product. MPEP 2113, citing In re Thorpe, 111 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985) states “[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production.
Regarding the argument of “significant synergistic effect”, it is noted that the prior art of record renders the claimed dry powder obvious, thus the results obtained are necessarily achieved by one of ordinary skill in the art using the said dry powder. It is also noted that CN ‘953 patent specifically teaches a composition in a dry powder form for inhalation comprising ambroxol hydrochloride, baicalin and an excipient that may be calcium phosphate to treat respiratory conditions. CN ‘953 also discloses that the ratio of baicalin to ambroxol may be 1:0.2-2. WU et al teach a dry powder composition comprising ambroxol hydrochloride and leucine which reaches and acts directly on the bronchi or on the damaged respiratory tract. Lipp et al provide teachings on the specifics of a dry powder for inhalation including the particle size. Thus, the combination of references would have readily led one of ordinary skill in the art to the claimed dry powder.
Regarding claims 11-12, a method of treating IPF comprising administration of an effective amount of the dry powder inhalant of claim 1, as stated above, the combination of refere4nces render the composition obvious. Specifically, CN ‘953 teach a dry powder composition comprising a combination of ambroxol hydrochloride and baicalin at the claimed ratios. P.R. Gupta and Zhao et al teach that both ambroxol and baicalin are effective medicaments in treating IPF. Both compounds are said to have anti-oxidative and anti-inflammatory effects and baicalin additionally having anti-infective effects. Thus, it would have been obvious to one of ordinary skill in the art to administer CN ‘953 dry powder composition to a subject in need of IPF treatment with a reasonable expectation of success. The one of ordinary skill in the art following the teachings of the references, would necessarily observe superior or synergistic results.
In this regard the courts have held that “The 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.” Atlas Powder Co. v. Ireco Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus, the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977). In In re Crish, 393 F.3d 1253, 1258, 73 USPQ2d 1364, 1368 (Fed. Cir. 2004), the court stated that “just as the discovery of properties of a known material does not make it novel, the identification and characterization of a prior art material also does not make it novel.” Therefore, absent evidence to the contrary, the compositions of the references of record would inherently result in synergistic effect in treating IPF. (See MPEP §2112).
Moreover, In re Huang, 40 USPQ2d 1685, 1688 states that even if the “modification results in great improvement and utility over the prior art, it may still not be patentable if the modification was within the capabilities of one skilled in the art, unless the claimed ranges “produce a new and unexpected result which is different in kind and not merely in degree from the results of the prior art.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (C.C.P.A. 1955); see In re Woodruff, 919 F.2d 1575, 1578, 16 USPQ2d 1934, 1936-37 (Fed.Cir. 1990).” Note similar language in In re Waymouth and Koury, 182 USPQ 290 (“a difference in kind, rather than in degree.”)
Applicants point to Tables 8, 9 and 10 of the Specification and some Figures as evidence of synergy. For example, Applicants point to Table 8 for showing a higher pulmonary function parameters in the group receiving both ambroxol hydrochloride (AH) and baicalin (BA) by inhalation or intravenous administration than those receiving one of BA an AH.
Applicants also point to Table 10 and Fig. 14 showing the total protein concentration in BALF and argue that “The total protein concentration in bronchoalveolar lavage fluid (BALF) is a key indicator of lung inflammation and permeability. …… The reduction rate of the BA/AH combination (38%) is significantly greater than the sum of the reduction rates of BA alone and AH alone (14%+15%=29%). This effect directly confirms that the combination of BA and AH produces synergistic effects over BA alone or AH alone” (See Remarks, pages 4-5).
The above arguments of evidence are not found convincing. Firstly, as stated above, the rejections clearly show that the claimed dry powder and a method of treating IPF were obvious to one of ordinary skill in the art. That is, evidence of unexpected results must be weighed against evidence supporting prima facie obviousness in making a final determination of the obviousness of the claimed invention. In re May, 574 F.2d 1082, 197 USPQ 601 (CCPA 1978). Looking at the prior art, it is known to make a dry powder comprising ambroxol hydrochloride, baicalin, leucin and phosphate for inhalation to treat respiratory diseases, as taught by CN ‘953. It also would have been obvious to use this dry powder composition to effectively treat IPF as taught by P.R. Gupta and Zhao et al.
Secondly, a true side by side comparison cannot be achieved when comparing the results from administration of two agents vs a single agent. Thus, comparing parameters such as PIF, Ti, Te, etc; as shown in Table 8 are not evidence of synergy. Thirdly, when considering the data provided with their standard deviations, the ranges of AH, BA or AH+BA DPI provide a large overlap. For example, PIF of AH DPI is 11.71± 3.34 thus resulting in a range of 8.37 to 15.05. The same parameter for BA+AH DPI is 12.43±6.08 thus resulting in a range of 6.35-18.51.
The same analogy applies to Tables 9 and 10.
Thirdly, regarding the inflammatory response, it is noted that P.R. Gupta and Zhao et al teach that ambroxol and baicalin both have anti-inflammatory effects on the respiratory tissues. Thus, two medicaments with different structures and mechanism of action having anti-inflammatory effect is expected to result in improved inflammatory response of the dry powder composition.
Next argument is that “In addition, the specific compound dry powder inhalant for treating idiopathic pulmonary fibrosis of the present application exhibits superior aerosol properties due to the specific formulation design. The inclusion of L-leucine at specific amount (10-40%) optimizes FPF values (e.g., 53.95 + 0.17% at 20% L-leucine), significantly improving drug deposition in the lungs compared to formulations without L-leucine (Table 7). Additionally, pulmonary administration via DPI increases drug retention in lung tissue and prolongs half-life compared to systemic injection (FIGs. 20-21)” (See Remarks, page 6).
This argument is also not found persuasive. The features Applicant is referring to as exhibiting superior aerosol properties are fully disclosed and taught by the prior art. It is not inventive to follow teachings in the prior art. For example, both Wu et al and Lipp et al teach a dry powder formulation with optimal FPF values comprising L-leucine in an amount of about 5% to about 30% by weight, a range that includes 10-40% and especially 20% as claimed and argued.
Applicants then points to the differences between the claimed limitations and the prior art. Applicants argue that “CN’227 lacks a disclosure on the baicalin, phosphate, their amounts, and the moisture content; Wu et al. lacks a disclosure on adding baicalin, phosphate or their amounts; and there is no disclosure for treating idiopathic pulmonary fibrosis in CN’227 and Wu et al. In addition, Wu et al. has repeatedly emphasized that the composition comprises particles of Ambroxol and/or hydrochlorides thereof as single active principle ….. and the formulation of the composition is designed to achieve the optimal administration form of ambroxol. Therefore, those skilled in the art would have no motivation to add other active ingredients to Wu et al.’s single active principle, nor can they predict whether it will affect the administration effect of ambroxol. Meanwhile, the composition of CN’227 consists of ambroxol hydrochloride, a dispersion glidant, and a diluent, which is defined in a closed-ended manner in both specification and claims” (See Remarks, Page 6).
The argument has been fully considered and found unpersuaive. The rejections are based on a combination of teachings. While one references’ s disclosure may be different in some way from the claimed product or method, it has been shown that one of ordinary skill in the art would have been motivated to combine the elements to arrive at the claimed invention with a reasonable expectation of success.
Additionally, Applicant appears to assign a very narrow skill set to one skilled in the art. In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the Examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). As indicated in the rejection supra, it would have been prima facie obvious to a person of ordinary skilled in the art at the time the invention was made to have combined the teachings of the cited references to arrive at the instant invention.
It is further noted that CN ‘227 was not relied upon for claims 11-12, Thus its lack of disclosure on treating IPF is irrelevant. The rejection of claims 11-12 is based on CN ‘953, Wu et al and P.R. Gupta and Zhao et al which teach the effect of ambroxol and baicalin on treating IPF. Further it is noted that CN ‘227 teach a dry powder composition comprising ambroxol hydrochloride, dispersing glidant and diluent, wherein the glidant is leucine. Lipp et al teach a dry powder formulation wherein the excipients may be magnesium phosphate and leucine.
The courts have held that “In determining obviousness, neither the particular motivation to make the claimed invention nor the problem the inventor is solving controls. The proper analysis is whether the claimed invention would have been obvious to one of ordinary skill in the art after consideration of all the facts.” (See MPEP § 2141).
Next argument is that “CN’953 teaches a composition of baicalin and ambroxol hydrochloride for chronic obstructive pulmonary disease (COPD), not IPF. IPF and COPD are distinct diseases with different pathological mechanisms. Thus, CN’953 provides no suggestion that this combination would be effective for IPF, let alone the remarkable synergistic therapeutic effect. In addition, although CN’953 discloses that the pharmaceutical composition comprises 5-120 parts by weight of ambroxol or a pharmaceutically acceptable salt thereof and 125-2000 parts by weight of baicalin, the actual mass ratio of baicalin to ambroxol or its pharmaceutically acceptable salt in the examples is calculated as 1:0.06, which does not fall within the range of 1:0.2 to 2 of the present application. Moreover, CN’953 does not teach or suggest the combination of baicalin, ambroxol hydrochloride, and L-leucine” (See Remarks, page).
The above argument is similarly unpersuasive. CN ‘953 teaches a dry powder composition comprising baicalin and ambroxol hydrochloride for treating - upper respiratory tract infections, chronic bronchitis, pneumonia and upper respiratory tract infections (such as acute and chronic bronchitis, bronchial asthma, bronchiectasis, tuberculosis, etc.) caused by sensitive bacteria such as thick sputum and difficulty in expectoration- (See abstract and body of the patent). While it does not expressly teach a method of treating IPF, the secondary references would have led one of ordinary skill in the art to the understanding that the same composition should be effective in treating IPF as they teach treating IPF with baicalin and ambroxol.
As to the disclosure of a narrower ratio, it is noted that a reference is relied upon for all that is disclosed and not specific embodiments or examples.
Regarding the argument that CN ‘953 does not teach adding L-leucine, it is noted that this element is taught by the secondary references including Lipp et al and Wu et al.
Claims 1, 3-9 and 11-12 are rejected.
THIS ACTION IS MADE FINAL. 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.
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/Mina Haghighatian/
Mina Haghighatian
Primary Examiner
Art Unit 1616