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 .
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 8 – 9 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for preventing or treating a liver disease in a subject where the disease does not include liver diseases with a significant genetic component, such as in autoimmune liver disease, does not reasonably provide enablement for preventing a liver disease in a subject where the disease includes a significant genetic component, such as autoimmune liver disease. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The claims are drawn to a method of preventing and/or treating a liver disease in a subject, which comprises administering to the subject a therapeutically effective amount of sustained-release tablet of drug IMM-H014 according to claim 1. The instant specification fails to provide information that would allow a person of skill in the art to practice the prevention of liver disease in a subject where the disease includes a significant genetic component, such as autoimmune liver disease.
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth by In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors: 1) the quantity of experimentation necessary; 2) the amount of direction or guidance provided; 3) the presence or absence of working examples; 4) the nature of the invention; 5) the state of the prior art; 6) the relative skill of those in the art; 7) the predictability of the art; and 8) the breadth of the claims. All of the Wands factors have been considered and those most relevant to the cited claims are discussed below.
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099, 1108, 427 F.2d 833, 839, 166 USPQ 18, 24 (1970). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
The breadth of the claims
The claims are thus very broad insofar as they recite “the liver disease is selected from the group consisting of autoimmune liver disease.” Moreover, autoimmune liver disease, represents a broad physiological response or symptom that can be triggered by different pathways. Thus autoimmune liver disease represents a very broad therapeutic target for treatment given the many pathways that are involved.
The amount of direction or guidance provided and the presence or absence of working examples
The disclosure does not provide representative examples which provide reasonable assurance to one skilled in the art that the instant method is effective in preventing the full scope of conditions related to liver diseases in a subject where the disease includes a significant genetic component, such as autoimmune liver disease, as claimed.
The specification has provided guidance for biochemical analysis of different tablet formulations of IMM-H014 in beagle dog models. See pages 7 – 15 examples 1 – 7. The specification does not provide guidance for preventing the full scope of conditions related to liver diseases in a subject where the disease includes a significant genetic component, such as autoimmune liver disease.
The nature of the invention, state and predictability of the art, and relative skill level
The invention relates to a method of preventing and/or treating a liver disease in a subject, which comprises administering to the subject a therapeutically effective amount of sustained-release tablet of drug IMM-H014 according to claim 1. The relative skill of those in the art is high being that of an MD or PHD. That factor is outweighed; however, by the unpredictable nature of preventing liver diseases in a subject where the disease includes a significant genetic component, such as autoimmune liver disease. As illustrative of the state of the art, the examiner cites the fact that while the prior art enables the use of IMM-H014 to target specific enzymes in specific pathways that lead to specific liver diseases, the basis of the instant invention relies on providing such alleviation through the administration of Imm-H014 as a broad treatment option for liver disease with significant genetic component such as autoimmune liver disease.
As taught by the state of the art of Horst et. al. ((2021), Antigen presentation, autoantibody production, and therapeutic targets in autoimmune liver disease, Cellular & Molecular Immunology, 18, 92 – 111) teach that autoimmune liver diseases (AILDs), such as autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC), are immune-mediated liver injuries that are characterized by lymphocyte infiltration into the liver, increases in circulating immunoglobulins, elevated liver enzymes, the generation of autoantibodies, and genetic risk factors, such as HLA loci associations that predispose individuals to developing AILDs. See page 92 column 1 paragraph 1. Thus, Horst et. al. suggest variability in genetic factors that predispose individuals to developing AILDs.
Moreover, Ellinghaus ((2022), How genetic risk contributes to autoimmune liver disease, Seminars in Immunopathology, 44, 397 – 410) teaches that the exact pathogenesis of autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC) is poorly understood. See page 397 column 1 paragraph 1. Furthermore, Ellinghaus teaches that the onset of PBC in particular is thought to be due to the interaction of environmental triggers and a genetic predisposition with the genetic risk being consistent with other complex autoimmune diseases. See page 398 column 1 paragraph 1. Moreover, Ellinghaus teaches that unfortunately, there are still no promising drugs that target the (unknown) key pathogenic processes in the early phase of disease progression. See page 398 column 1 paragraph 2. Additionally, Ellinghaus teaches that one of the greatest challenges in genetic epidemiological studies remains deriving a functional biological interpretation of the results from GWAS. See page 398 column 2 paragraph 1. Thus Ellinghaus suggest that there is no known key pathogenic processes in the early phase of disease progression. As a consequence, Ellinghaus suggest that it would not be feasible to prevent autoimmune liver diseases using a single therapeutic agent.
Furthermore, there is no way to predict based on the state of the prior art or the teachings in the specification whether or not the claimed skeleton sustained-release tablet comprising IMM-H014 would be effective for the prevention of liver disease in a subject where the disease includes a significant genetic component, such as autoimmune liver disease, as recited in the claims.
The quantity of experimentation necessary
While the prevention of autoimmune liver disease is theoretically possible, as a practical matter without a known key target in the pathogenic processes in the early phase of disease progression it would be impossible to prevent a liver disease such as autoimmune liver disease with a single therapeutic agent as recited in the claims.
The amount of experimentation needed to determine how to prevention of liver disease in a subject where the disease includes a significant genetic component, such as autoimmune liver disease. As stated, in the state of art there is currently no known key pathogenic processes in the early phase of disease progression. Thus, the initial studies would involve the determination of the key pathogenic processes in the early phase of disease progression. Moreover, the types of studies that would be necessary to establish the prevention would include studies in to the individual situations and specific contexts in which the autoimmune liver disease involve.
Considering autoimmune liver disease the complexity of the underlying mechanisms, and the high unpredictability in the art, and the lack of guidance provided in the specification, one of ordinary skill in the art would be burdened with undue experimentation to practice the invention commensurate in scope with the instant claims. Since the specification does not demonstrate prevention of liver disease in a subject where the disease includes a significant genetic component, such as autoimmune liver disease the examiner maintains that the instant claims are not enabled for the full scope of claims 8 – 9 in light of the entire disclosure.
Accordingly, claims 8 – 9 do not comply with the enablement requirement of §112, since to practice the invention claimed in the patent a person of ordinary skill in the art would have to engage in undue experimentation, with no assurance of success.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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 – 5, and 7 – 9 are rejected under 35 U.S.C. 103 as being unpatentable over International Publication Number WO 2021/103749 A1 to Wu et. al. (Wu’749; English Machine Language Translation (EMLT) used) in view of International Publication Number WO 2005/039561 A1 to Wu et. al. (Wu’561; English Machine Language Translation used).
Regarding claims 1 – 5, and 7 – 9, Wu’749 teach levorotatory bicyclic morpholine and its pharmaceutically acceptable salts, preparation, and its method of application in preparing drugs for the prevention and/ or treatment of liver disease. See EMLT document page 2 paragraph 0001. Wu’749 teach that bicyclol is the first Class I chemical drug for treating hepatitis developed with good hepatoprotective and enzyme-lowering effects and certain anti-hepatitis virus activity. See EMLT page 4 paragraph 0003. Furthermore, Wu’749 teach that the bicyclic alcohols have poor water solubility, resulting in low bioavailability. See EMLT page 5 paragraph 0004. Moreover, Wu’749 teach that, the bicyclic alcohol scaffold was optimized to result in the bicyclic morpholine compound. See EMLT page 5 paragraph 0004. Thus Wu’749 suggest that the bicyclic morpholine compound is a bioisostere of bicyclic alcohol.
Wu’749 teach that levorotatory bicyclomorpholine and its salts exhibited better pharmacological activity and pharmacokinetic properties in anti-inflammatory and hepatoprotective effects than the racemic and dextrorotatory forms and their salts. See EMLT document page 6 paragraph 0004. Additionally, Wu’749 teach that liver-related diseases mentioned in the disclosure are selected from liver injury-related diseases and hepatitis-related diseases, specifically including: hepatitis A, hepatitis B, hepatitis C, drug induced liver disease, alcoholic liver disease, non-alcoholic liver disease, autoimmune liver disease, liver fibrosis, cirrhosis, and liver failure. See EMLT page 28 paragraph 0032. See claims 8 – 9 limitation for a method of treating a liver disease in a subject where the liver-disease is selected from the group consisting of hepatitis A, hepatitis B, hepatitis C, drug induced liver disease, alcoholic liver disease, non-alcoholic liver disease, autoimmune liver disease, liver fibrosis, cirrhosis, and liver failure.
Additionally, Wu’749 teach that the compounds of the discourse which include the (+) IMM-H014 compound, can have the dosage form of a liquid, solid, or semi solid. See EMLT page 17 paragraph 0022. Moreover, Wu’749 teach that the solid dosage forms can be tablets (including regular tablets, enteric-coated tablets, lozenges, dispersible tablets, chewable tablets, effervescent tablets, and orally disintegrating tablets), capsules (including hard capsules, soft capsules, and enteric-coated capsules), granules, powders, microcapsules, droplets, suppositories, films, patches, aerosols, and sprays, etc.; semi-solid dosage forms can be ointments, gels, pastes, etc. See EMLT page 18 paragraph 0022.
Furthermore, Wu’749 teach that the compounds of the discourse can be formulated into conventional formulations, as well as sustained-release formulations, controlled-release formulations, targeted formulations, and various microparticle delivery systems. See page 19 paragraph 0023. See claim 1 limitation for a skeleton sustained release tablet. Moreover, Wu’749 teach that to formulate the compounds of the present invention into tablets, a wide variety of excipients known in the art can be used, including diluents, binders, wetting agents, disintegrants, lubricants, and solubilizers. See EMLT page 19 paragraph 0024. Wu’749 teach that diluents can be selected from a group comprising starch, sucrose, lactose, mannitol, sorbitol, microcrystalline cellulose, wetting agents can be water, ethanol; binders can be starch paste, microcrystalline cellulose, hydroxypropyl methyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, etc; disintegrants can be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose; lubricants and cosolvents can be talc, silica, stearate, etc. See EMLT page 20 paragraph 0024. See claim 1 limitation for a skeleton sustained-release tablet comprising skeleton material, diluent, glidant, and lubricant. See claim 2 limitation for a skeleton sustained-release tablet comprising hydroxypropyl methyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone. See claim 4 limitation for a skeleton sustained-release tablet characterized by diluent is one or a mixture selected from the group consisting of lactose, microcrystalline cellulose, starch, mannitol, sorbitol, sucrose, and calcium dihydrogen phosphate; the lubricant is one or a mixture of more than one selected from the group consisting of talc, and stearic acid. See claim 7 limitation for a method where the binder is selected from starch slurry, and water, ethanol.
Specifically, Wu’749 teach the synthesis of the levorotatory bicyclomorpholine compound whose intermediate is the racemic and dextrorotatory forms of structure
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. See untranslated Wu’749 page 6. See claim 1 limitation for IMM-H014 as shown in Formula 1. Moreover, Wu’749 teach a pharmacological experiment where the effects of IMM-H014 optical enantiomers on phytohemagglutinin (ConA)-induced acute immune liver injury in SPF-grade male ICR mice. See EMLT page 45 – 53 paragraphs 0050 – 0062. Additionally, Wu’749 teach in this study that the mice were randomly divided into 5 groups after acclimatization: blank control group, Con A model group, (+)IMM-H014 200mg/kg group, (-)IMM-H014 200mg/kg group, and (±)IMM-H014 200mg/kg group, with 10 mice in each group. See EMLT page 46 paragraph 0052. Moreover, Wu’749 teach in this study Both (+)IMM-H014 and (-)IMM-H014 significantly reduced ConA-induced serum ALT elevation (P<0.001), with ALT reduction rates of 95.3% and 97.3%, respectively, reducing ALT levels to the level of the blank control group. See EMLT page 52 paragraph 0059.
Additionally, Wu’759 teach that both (+)IMM-H014 and (-)IMM-H014 showed significant protective effects against ConA-induced immune liver injury, with (-)IMM-H014 exhibiting slightly better activity than (+)IMM-H014. See EMLT page 52 paragraph 0059. Furthermore, Wu’749 teach that (+)IMM-H014, (-)IMM-H014 and (±)IMM-H014 all reduced the level of serum AST induced by ConA. See EMLT page 56 paragraph 0064. Additionally, Wu’749 teach that compared with the model group, the percentage reduction in AST was 44.8%, 72.9% and 22.2%, respectively with the (-)IMM-H014 group showing a statistically significant difference compared with the model group (P<0.01). See EMLT page 56 paragraph 0064. Thus, Wu’749 suggest that the optically pure enantiomers of (-)IMM-H014 and (+)IMM-H014 have similar pharmacokinetic effects in vivo.
However, Wu’749 fail to recite a skeleton sustained-release tablet comprising the (+) IMM-H014 with a weight percentage composition as follows: 5% to 25% of IMM-H014 as shown in Formula 1 or pharmaceutically acceptable salt thereof as active ingredient, 10% to 80% of a skeleton material, 10% to 75% of a diluent, 0.1 % to 5% of a glidant, and 0.5% to 5% of a lubricant. See examined claims 1 limitation. Furthermore, Wu’749 fail to recite a skeleton sustained-release tablet where the hydroxypropyl methylcellulose comprises those with viscosity type of K4M, K15M, or K100M. See examined claims 3 limitation. Moreover, Wu’749 fail to recite a method for preparing a skeleton sustained-release tablet comprising the (+) IMM-H014. See examined claims 5 – 7.
Nevertheless, Wu’561 teach micronized bicyclol, a poorly soluble drug; a method for preparing the micronized bicyclol; and an oral extended-release formulation of bicyclol, and a method for preparing such an extended-release formulation. See EMLT page 2 paragraph 0002. Wu’561 teach bicyclol is a novel anti-hepatitis drug developed by the Institute of Materia Medica, Chinese Academy of Medical Sciences. See EMLT page 10 paragraph 0007. Furthermore, Wu’561 teach a method for preparing a bicyclic alcohol oral matrix sustained release formulation. See EMLT page 20 paragraph 0017. Wu’561 teach an embodiment where the proportion of the micronized bicyclol in the formulation is 5 – 30 %. See EMLT page 15 paragraph 0013. See claim 1 limitation for a skeleton sustained-release tablet where the active ingredient is from 5 % to 25 % weight percent. Additionally, Wu’561 teach an embodiment where the framework materials for the formulation includes hydroxypropyl methylcellulose (HPMC) with a viscosity of K4M, K15M, or K100M used in the formulation ranges from 5% to 70%. See EMLT page 20 paragraph 0017. See claim 1 limitation for a skeleton sustained-release tablet where the skeleton material is 10% to 80%. See claim 3 limitation for a skeleton sustained-release tablet where the hydroxypropyl methylcellulose comprises those with viscosity type of K4M, K15M, or K100M.
Specifically, Wu’561 teach the direct compression method where HPMC (K4M) and lactose are sieved through an 80-mesh sieve, thoroughly mixed with micronized bicyclol, micronized silica gel and magnesium stearate are added and mixed evenly, then compressed into tablets with a tablet weight of approximately 355mg. See EMLT page 23 paragraph 0049. See claim 1 limitation for a skeleton sustained-release tablet with a glidant. See claim 4 limitation for a skeleton sustained-release tablet where the glidant is micro-powder silica gel. See claim 5 limitation for a method of preparing a skeleton sustained-release tablet through powder direct compression with the steps of the HPMC (K4M) and lactose through mixed with the active ingredient, then micronized silica gel and magnesium stearate are added and mixed again before being compressed into tablets.
Moreover, Wu’561 teach the wet granulation method where HPMC (K4M) and lactose are passed through an 80-mesh sieve and thoroughly mixed with the active ingredient, before an appropriate amount of water is added to form a soft mass, which is then granulated through a 16-mesh sieve. See EMLT page 24 paragraph 0020. Furthermore, Wu’561 teach that the wet granules are dried at 60°C for 2 hours, granulated through an 18-mesh sieve, and then mixed with micronized silica gel and magnesium stearate before the mixture is then compressed into tablets. See EMLT page 24 paragraph 0020. See claim 7 limitation for a method of preparing a skeleton sustained-release tablet through wet granulation method with the steps of the HPMC (K4M) and lactose being passed through sieve before being mixed with a binder which is dried and granulated before being mixed with micronized silica gel and magnesium stearate before the mixture is then compressed into tablets. Additionally, Wu’561 teach prescription 1 comprising 35 mg or 10 % of the active ingredient, 55 mg HPMC (K4M), lactose 240 mg, micronized silica gel 7 mg, and magnesium stearate 3 mg to make a tablet of total weight of approximately 340 mg. See EMLT pages 55 – 57 paragraph 0072 – 0078.
Regarding claim 1 limitation for a skeleton sustained-release tablet with the composition of 5% to 25% of IMM-H014 as active ingredient, 10% to 80% of a skeleton material, 10% to 75% of a diluent, 0.1 % to 5% of a glidant, and 0.5% to 5% of a lubricant; as taught above, Wu’561 teach prescription 1 comprising 35 mg or 10 % of the active ingredient, 55 mg HPMC (K4M), lactose 240 mg, micronized silica gel 7 mg, and magnesium stearate 3 mg to make a tablet of total weight of approximately 340 mg. Given that the relative skill of one of ordinary skill in the art is relatively high being that of a MD or PhD it would have been within the purview of such artisan to convert the recited mg to weight percentage by dividing the mg of the component by the approximate weight of the tablet then multiplying by 100. Thus it would have obvious the Wu’561 teach a formulation where the active ingredient is 10 %;the skeleton material, which is HPMC (K4M), is 16 %; the diluent, which is lactose, is 70.5 %; the glidant, which is micronized silica gel, is 2 %; and the lubricant, which is magnesium stearate, is 0.88 %. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). See MPEP 2144.05 (I).
With regards to claims 5 and 7 limitation for a method for preparing the skeleton sustained-release tablet comprising the step of weighing the components; given that the prior art of Wu’561 teach a tablet composition comprising specific mass of each component and given that the relative skill of one of ordinary skill in the art is relatively high being that of a MD or PhD it would have been within the purview of such artisan that there is an implicit step of measuring or weighing of the components before the mixing.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to take the compound of Wu’749 that is the (+) IMM-H014 optical isomer in view of Wu’561 that is to formulate the (+) IMM-H014 optical isomer as a skeleton sustained-release tablet comprising the tablet components at the amounts recited. One of ordinary skill in the art would have been motivated to make this modification because the (+) IMM-H014 optical isomer had comparable pharmaceutical effect to the (-) IMM-H014 isomer in a liver disease mouse model. Additionally, one of ordinary skill in the art would have been motivated to make this modification because the (+) IMM-H014 is a soluble bioisostere for bicyclic alcohol, that is bicyclol. One of ordinary skill in the art would have a reasonable expectation of success because the bicyclol was able to be formulated into a skeleton sustained-release tablet; thus, the expectation is that (+) IMM-H014 a compound of similar structure can be formulated into a skeleton sustained-release tablet.
Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over International Publication Number WO 2021/103749 A1 to Wu et. al. (Wu’749; English Machine Language Translation (EMLT) used) in view of International Publication Number WO 2005/039561 A1 to Wu et. al. (Wu’561; English Machine Language Translation used) as applied to claims 1 – 5, and 7 – 9 above, and further in view of Šantl et. al. ((2011), A compressibility and compactibility study of real tableting mixtures: The impact of wet and dry granulation versus a direct tableting mixture, International Journal of Pharmaceutics, 414, 131 – 139.
The teachings of Wu’749 and Wu’561 as they relate to claims 1, from which claim 6 depends, are given previously in this office action and are fully incorporated here.
However, the prior art of Wu’749 and Wu’561 fail to recite a method for preparing a skeleton sustained-release tablet comprising the (+) IMM-H014 using the dry granulation method. See claim 6 limitation.
Nevertheless, Šantl et. al. teach that the successful compaction and tableting of pharmaceutical powders requires a profound understanding of the fundamental properties of powders. See page 131 column 1 paragraph 1. Šantl et. al. teach that in the pharmaceutical industry, the preferred tablet production method is direct tableting; however, it is often necessary to improve the material’s compaction and flow properties in order to obtain uniform die-filling and to produce tablets of adequate quality. See page 131 column 1 paragraph 1. Moreover, Šantl et. al. teach that these properties are commonly enhanced by converting fine powders into larger agglomerates by the process of wet or dry granulation. See page 131 column 1 paragraph 1. Šantl et. al. teach that dry granulation consists of a compaction step followed by a milling step. See page 131 column 1 paragraph 1.
In particular, Šantl et. al. teach that before preparation of the mixture, all materials were sieved manually through a sieve with a mesh size of 0.8 mm and the weighted amounts of powders were the same for all mixtures: lactose monohydrate (7.32 kg), microcrystalline cellulose (2.80 kg), Povidone K25 (370 g), and Primojel (580 g). See page 132 column 2 paragraph 1. Next, Šantl et. al. teach that weighted powders were mixed in a 50 L biconical mixer before roller compaction and granulation by an oscillating sieve. See page 132 column 2 paragraph 4. Furthermore, Šantl et. al. teach that the obtained granules, were sieved before being mixed with Aerosil 200 (37.2 g) in a 50 L biconical mixer next Aerosil 200, magnesium stearate (74.4 g) was added and mixing was continued for 2 min at 10 rpm before being in-die or out of die compressed. See page 132 column 2 paragraph 2.
Regarding claim 6, limitation for a method for preparing a skeleton sustained-release tablet comprising the (+) IMM-H014 using the dry granulation method with active steps of weighing the components; mixing the active material + skeleton material + diluent; performing the dry granulation, adding the glidant and lubricant, before pressing into tablets; as taught above, Šantl et. al. does teach the active steps of mixing, dry granulation, 2nd mixing, and pressing. Furthermore, given that the relative skill of one of ordinary skill in the art is relatively high being that of a MD or PhD and the teachings of Wu’561 for the wet granulating method and direct compression method; the method steps for the dry granulation method as recited in claim 6 would have been obvious to one of ordinary skill in the art.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to take the compound of Wu’749 that is the (+) IMM-H014 optical isomer in view of Wu’561 that is to formulate the (+) IMM-H014 optical isomer as a skeleton sustained-release tablet comprising the tablet components at the amounts recited,
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1 –5, and 7 – 9 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 – 15 of U.S. Patent No. US Patent No. US 12630520 B2 to Wu et.al. (Wu’520) in view of International Publication Number WO 2021/103749 A1 to Wu et. al. (Wu’749; English Machine Language Translation (EMLT) used) in view of International Publication Number WO 2005/039561 A1 to Wu et. al. (Wu’561; English Machine Language Translation used).
Wu’520 recite a left-handed bicyclic morpholine and a pharmaceutically acceptable salt thereof, characterized in that the structure of the left-handed bicyclic morpholine is shown by Compound 5, and the pharmaceutically acceptable salt has a structural formula (I):
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. See reference claim 1. Wu’520 further recite the left-handed bicyclic morpholine as a salt using inorganic acids or organic acids. See reference claims 2 – 4. Additionally, Wu’520 recite a process of preparing the left-handed bicyclic morpholine and the pharmaceutically acceptable salt thereof according to claim 1, characterized in that it comprises steps where the formation of IMM-H014 is an intermediate. See reference claim 5. See examined claim 1. Moreover, Wu’520 recite a pharmaceutical composition, characterized in that it comprises the left-handed bicyclic morpholine and the pharmaceutically acceptable salt thereof according to (reference) claim 1, and optionally one or more pharmaceutically acceptable carriers or excipients. See reference claims 6, and 10 – 12. Furthermore, Wu’520 recite a method of treating liver-related diseases comprising administering a compound of (reference) claim 1 or (reference) claim 4. See reference claims 7 – 9, and 13 – 15. See examined claims 8 – 9.
However, Wu’520 fail to recite a skeleton sustained-release tablet comprising the righthanded bicyclic morpholine with the recited weight percentages. See examined claims 1 – 4. Moreover, Wu’520 fail to recite a method for preparing a skeleton sustained-release tablet comprising the righthanded bicyclic morpholine. See examined claims 5 and 7. Furthermore, Wu’520 fail to recite a method of preventing or treating a liver disease comprising administering a skeleton sustained-release tablet comprising the righthanded bicyclic morpholine. See examined claims 8 – 9.
Nevertheless, the teachings of Wu’749 and Wu’561 as they relate to the prior art rejections of examined claims 1 – 5, and 7 – 9, are given previously in this office action and are fully incorporated here.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to apply the invention of Wu’520 for a left handed bicyclic morpholine compound capable of being formulated into a pharmaceutical composition and treating/preventing liver disease in view of Wu’579 that is to substitute the right handed bicyclic morpholine compound, in further view of Wu’561 that is to formulate the right handed bicyclic morpholine compound as a skeleton sustained-release tablet. One of ordinary skill in the art would have been motivated to make this modification because the (+) IMM-H014, or right handed bicyclic morpholine had comparable pharmaceutical effect to the (-) IMM-H014 isomer in a liver disease mouse model. Additionally, one of ordinary skill in the art would have been motivated to make this modification because the (+) IMM-H014 is a soluble bioisostere for bicyclic alcohol, that is bicyclol. One of ordinary skill in the art would have a reasonable expectation of success because the bicyclol was able to be formulated into a skeleton sustained-release tablet; thus, the expectation is that (+) IMM-H014 a compound of similar structure can be formulated into a skeleton sustained-release tablet.
Claim 6 is rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 – 15 of U.S. Patent No. US Patent No. US 12630520 B2 to Wu et.al. (Wu’520) in view of International Publication Number WO 2021/103749 A1 to Wu et. al. (Wu’749; English Machine Language Translation (EMLT) used), International Publication Number WO 2005/039561 A1 to Wu et. al. (Wu’561; English Machine Language Translation used) and Šantl et. al. ((2011), A compressibility and compactibility study of real tableting mixtures: The impact of wet and dry granulation versus a direct tableting mixture, International Journal of Pharmaceutics, 414, 131 – 139.
Wu’520 recite a left-handed bicyclic morpholine and a pharmaceutically acceptable salt thereof, characterized in that the structure of the left-handed bicyclic morpholine is shown by Compound 5, and the pharmaceutically acceptable salt has a structural formula (I):
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250
258
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. See reference claim 1. Wu’520 further recite the left-handed bicyclic morpholine as a salt using inorganic acids or organic acids. See reference claims 2 – 4. Additionally, Wu’520 recite a process of preparing the left-handed bicyclic morpholine and the pharmaceutically acceptable salt thereof according to claim 1, characterized in that it comprises steps where the formation of IMM-H014 is an intermediate. See reference claim 5. See examined claim 1. Moreover, Wu’520 recite a pharmaceutical composition, characterized in that it comprises the left-handed bicyclic morpholine and the pharmaceutically acceptable salt thereof according to (reference) claim 1, and optionally one or more pharmaceutically acceptable carriers or excipients. See reference claims 6, and 10 – 12. Furthermore, Wu’520 recite a method of treating liver-related diseases comprising administering a compound of (reference) claim 1 or (reference) claim 4. See reference claims 7 – 9, and 13 – 15.
However, Wu’520 fail to recite a method for preparing a skeleton sustained-release tablet comprising the righthanded bicyclic morpholine using the dry granulation method. See examined claim 6.
Nevertheless, the teachings of Wu’749, Wu’561, and Šantl et. al. as they relate to the prior art rejections of examined claim 6, are given previously in this office action and are fully incorporated here.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to apply the invention of Wu’520 for a left handed bicyclic morpholine compound capable of being formulated into a pharmaceutical composition and treating/preventing liver disease in view of Wu’579 that is to make a right handed bicyclic morpholine compound, in view of Wu’561 that is to formulate the right handed bicyclic morpholine compound as a skeleton sustained-release tablet in further view of Šantl et. al. , that is to use the dry granulation method. One of ordinary skill in the art would have been motivated to make this modification to improve the material’s compaction and flow properties. One of ordinary skill in the art would have a reasonable expectation of success because these properties are commonly enhanced by converting fine powders into larger agglomerates by the process of wet or dry granulation.
Conclusion
Claims 1 – 9 are rejected.
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/DAWANNA SHAR-DAY WHITE/Examiner, Art Unit 1627
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