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 .
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.
This office action is a response to applicant’s communication submitted February 22, 2024. This application is a CON of PCT/CN2022/114489 filed 08/24/2022 and claims foreign priority to CN 202110983725.7 filed 08/25/2021.
Claims 1-13 are pending in this application.
Drawings
The drawings are objected to because:
In Figure 19A K4 and DK4 should have brackets signifying they are polymers.
In figures 19A-19C, the terminal OH should be outside of the bracket to demonstrate there is always a reducing end hydroxyl group in the oligosaccharide.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The disclosure is objected to because of the following informalities:
On page 2 of the instant specification, the structure
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appears at the bottom of the page. However, the terminal OH should be outside of the bracket to demonstrate there is always a reducing end hydroxyl group in the oligosaccharide.
Appropriate correction is required.
Claim Objections
Claim 1 is objected to because of the following informalities:
Claim 1 shows the structure
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however the terminal OH should be outside of the bracket to demonstrate there is always a reducing end hydroxyl group in the oligosaccharide.
Appropriate correction is required.
Claim Interpretation
With respect to instant claim 11, which is directed to a pharmaceutical composition and recites the phrase “for treating nervous system diseases”. The Examiner notes that it is well settled that “intended use” of a composition or product, e.g., “for treating”, will not further limit claims drawn to a composition, so long as the prior art discloses the same composition comprising the same ingredients in an effective amount, as the instantly claimed (See MPEP 2111.02 (II)). Additionally does not recite any specific type of drug formulation, thus the broadest reasonable interpretation of the claim includes making the compound of claim 1 itself.
Claim Rejections - 35 USC § 112 (b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 2-10 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 2 recites inter alia wherein step 3 comprises “6-O-sulfation…., and then 6-O-sulfation”. Thus step 3 appears to make 6-O-sulfation an alternative limitation in the beginning and then makes it a requirement in the end. It is unclear whether performing 6-Osulfation initially would still require 6-O-sulfation, which is redundant. Thus, the lack of clarity renders the claim indefinite. Claims 3-10 which depend from claim 2 are similarly rejected.
Claim 6 contains the trademark/trade name Bio-Gel®. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe a gel filtration source and, accordingly, the identification/description is indefinite.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 11-13 are rejected under 35 U.S.C. 101 because:
The claimed invention is directed to non-statutory subject matter. The claim(s) does/do not fall within at least one of the four categories of patent eligible subject matter because the claims are “use” claims. one cannot claim a new use per se, because it is not among the categories of patentable inventions (process, machine, manufacture, or composition of matter) specified in 35 U.S.C. § 101.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1 and 11 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Bedini (Angew. Chem. Int. Ed., 2011, cited on PTO-892).
Bedini teaches the following disaccharides
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(pg. 6162, col. 2, figure 3), which anticipate claim 1. The broadest reasonable interpretation of claim 11 includes preparation of the compound itself, as discussed in the claim interpretation section.
Claims 1 and 11 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Huckerby (Eur. J. Biochem., 2001, cited on PTO-892).
Huckerby teaches the following sulfated oligosaccharides
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(pg. 1182, col. 1, figure 1). The broadest reasonable interpretation of claim 11 includes preparation of the compound itself, as discussed in the claim interpretation section.
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.
Claims 2-5 and 7-10 are rejected under 35 U.S.C. 103 as being unpatentable over Huckerby (Eur. J. Biochem., 2001, cited on PTO-892) as applied to claim 1 above in view of Volpi (Carbohydrate Polymers, 2005, cited on PTO-892), Sugiura (J. Biological Chem., 2012, cited in PTO-892), D’Ambrosio (Scientific Reports, 2020, cited on PTO-892), Xu (International Journal of Biological Macromolecules, 2019, cited on PTO-892), Wang (CN 111741963, IDS filed February 22, 2024, English translation provided on PTO-892), and Liu (CN 111154819, IDS filed February 22, 2024, English translation provided on PTO-892).
Regarding claims 2: Huckerby teaches the preparation of chondroitin sulfate oligosaccharides as discussed above. Huckerby teaches the method comprises enzymatic digestion of chondroitin sulfate with 1 U/100mg chondroitin ABC endolyase or chondroitin ACII lyase for 15 hours (pg. 1182, col. 2, para. 3). The enzyme was inactivated by heating at 100 C for 1 min (pg. 1182, col. 2, para. 3). The oligosaccharides were isolated via chromatography on a Spherisorb S5 column, column eluate was monitored at 232 nm, followed by pooling oligosaccharides and subjected to a BioGel P-2 column, then lypholized (pg. 1182, col. 2, para. 3-). Huckerby teaches the lyase enzymes convert the uronic acid residue at the cleavage site into a D4,5-unsaturated uronic acid (DUA) (pg. 1181, col. 2, para. 4).
Huckerby does not teach preparing the compounds starting from K4 polysaccharide, defructosylating to obtain DK4, degrading with a sulfate degrading enzyme and modifying the oligosaccharide by 6-O sulfation.
However, Xu teaches polysaccharide K4 expressed fromE. coli K4 has a similar structure with chondroitin, which can be used as a precursor to produce chondroitin sulfates (abstract). Xu teaches chondroitin sulfate from animal sources has the problem of mixed products and high risk of viral contamination (pg. 702, col. 1, para. 1). chondroitin sulfate products can be prepared by subsequent treatments of defructosylation and sulfation (pg. 702, cols. 1-2, bridging para.). K4 polysaccharide has a chondroitin-like backbone, which provides a potential alternative to the traditional extraction from animal tissues (pg. 704, col. 1, last para.). Xu teaches Chondrotin sulfate products can be prepared from K4 polysacchairde by subsequent treatments of defructosylation and sulfation (pg. 702, cols. 1-2, bridging para.). K4 polysaccharide is converted to defructosylated K4 (DK4) (abstract). The conversion is performed by treating the K4 polysaccharide with trifluoroacetic acid, the product was dialyzed and lyophilized (pg. 703, col. 2, para. 3).
Wang teaches the preparation of a low molecular weight chondroitin sulfate (LMWCS) using macromolecular chondroitin sulfate as the raw material (abstract). Wang teaches the preparation of chondroitin sulfate disaccharide (abstract). Wang teaches the composition comprising the low molecular weight chondroitin sulfate repairs chondrocytes damaged by hydrogen peroxide and can be used for the treatment of joint damage, cosmetics, food, and other important raw materials. Wang teaches that high molecular weight CS has high apparent viscosity, complex structure, and is not easy to pass through the cell membrane, and has low bioavailability (English translation, background technique, para. 2). Wang teaches LMWCS is generally prepared by the degradation of CS products, mainly including acid hydrolysis, alkaline hydrolysis and enzymatic methods (English translation, background technique, para. 4). There are many impurities in the acid degradation reaction product and it is not easy to remove (English translation, background technique, para. 4). During the reaction process, the sulfonic acid group on chondroitin sulfate will also fall off to varying degrees, and cause environmental pollution (English translation, background technique, para. 4).
Volpi teaches a method of defructosylating non-sulfated fructosylated K4 polysaccharide comprising acid treatment at pH 3.0 (pg.328, col. 1, last para.). Volpi then teaches the enzymatic digestion of defructosylated K4 comprising using chondroitinase ABC (pg. 328, col. 2, para. 2). Volpi teaches this process results in
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, which is the disaccharide of defructosylated K4 (i.e. DK4, pg. 329, figure 1B).
He teaches the conversion of chondroitin to chondroitin 4-sulfate in the presence of PAPS using C4ST-1 enzyme (pg. 3, figure 2).
Sugiera teaches chondroitin-4-sulfotransferase1(C4ST-1),chondroitin-6-sulfotransferase1(C6ST-1), and N-acetylgalactosamine4-sul fate 6-sulfotransferase can be used to sulfonate the 4 and 6 positions of the GalNAC moiety in chrondroitin (abstract).
Liu teaches a non-animal source low molecular weight heparin and a preparation method and application thereof (English translation, abstract). Liu demonstrates the sequential sulfation of 2 and 6 positions using enzymatic methods after the polymer is degraded (English translation, pg. 4, steps 1-5). Liu teaches sulfate group donor PAPS is added 1.1 to 1.5 times the molar mass of the glucosamine residue contained in the intermediate (English translation, pg. 5, para. 3). Thus Liu establishes that enzymatic methods are applicable to degraded polysaccharides. Use of known technique to improve similar devices (methods, or products) in the same way is prima facie obvious (See MPEP 2143 (I)).
D’Ambrosio teaches a method of preparing high molecule weight chondroitin from K4 polysaccharide (abstract). D’Ambrosio teaches purification methods comprising centrifugation, precipitation, and ultrafiltration methods ranging from 30 kDA to 5 kDa (pg. 4, figure 1). D’Ambrosio teaches hydrolysis (i.e. defructosylation) can be performed with heating (pg. 3, paras. 2-3).
Taken together it would have been prima facie obvious to a person of ordinary skill in the art to modify the method of Huckerby, such that the compounds are prepared starting from K4 polysaccharide, defructosylating to obtain DK4, degrading with a sulfate degrading enzyme and modifying the oligosaccharide by 4-O, 6-O sulfation using chondroitin-4-sulfotransferase1(C4ST-1) and chondroitin-6-sulfotransferase1(C6ST-1) as taught by Xu, Wang, Volpi, He, Sugiera, and Liu. A person of ordinary skill in the art would have had the motivation to do so to prepare low molecular CS oligosaccharides from a non-animal source without risk of sulfate groups falling off during degradation and to prepare oligosaccharides that are free of contamination to be used in joint injury compositions. A person of ordinary skill in the art would have a reasonable expectation of success as each elementary step involved in known in the prior art. Selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results (See MPEP IV (c)).
Regarding claim 3: Huckerby does not teach wherein the K4 is dissolved in an acid solution, heated, cooled, and dialyzed to obtain DK4.
However, Volpi teaches a method of defructosylating non-sulfated fructosylated K4 polysaccharide comprising acid treatment at pH 3.0 (pg.328, col. 1, last para.). Volpi teaches the defructosylated K4 was obtained by dialysis and lyophilization (pg. 328, col. 2, para. 2). D’Ambrosio teaches hydrolysis (i.e. defructosylation) can be performed with heating and then cooling (pg. 3, paras. 2-3).
Taken together it would have been prima facie obvious to utilize the conditions of heating, cooling, and dialyzing as taught by Volpi and D’Ambrosio. A person of ordinary skill in the art would have had the motivation to do so with a reasonable expectation of success in order to defructosylate K4 and isolate DK4, as these conditions have been utilized to do so in the prior art.
Regarding claims 4-5: Huckerby teaches the method comprises enzymatic digestion of chondroitin sulfate with 1 U/100mg chondroitin ABC endolyase or chondroitin ACII lyase for 15 hours in a buffer (chABC in a buffer, wherein enymolysis occurs, the buffer is necessarily an enzymolysis buffer,pg. 1182, col. 2, para. 3). The enzyme was inactivated by heating at 100 C for 1 min (pg. 1182, col. 2, para. 3).
Huckerby does not teach undergoing solid-liquid separation and collecting the filtrate.
However, Liu teaches that following enzymatic hydrolysis, oligosaccharides can be isolated via alcohol precipitation (i.e. filtration, English translation, pg. 6, middle of page).
Taken together it would have been prima facie obvious to isolate the degraded oligosaccharides using filtration as suggested by Liu. A person of ordinary skill in the art would have had the motivation to do so with a reasonable expectation of success as this is a known technique in the art for isolating oligosaccharides following enzymatic degradation in order to purify the oligosaccharides.
Regarding claims 7 and 9-10: As discussed above, Huckerby teaches the method comprises enzymatic digestion of chondroitin sulfate with 1 U/100mg chondroitin ABC endolyase or chondroitin ACII lyase for 15 hours (pg. 1182, col. 2, para. 3).
Huckerby does not specify the the ratio of degrading enzyme to DK4, the ratio of sulfate donor 3’-phosphoadenosine-5’phosphosulfate (PAPS) to sulfotransferase, or the ratio of chondroitin oligosaccharide to sulfotransferase.
However, Wang teaches the operating conditions of the enzymatic hydrolysis reaction are as follows: the added amount of the chondroitin sulfate lyase relative to each liter of fermentation broth is 100-300 U/L (English translation, pg. 6, para. 4). Sugiura teaches the amount of sulfation enzyme varies dependent on amount required for catalyzing the transfer of sulfate per minute (pg. 43392, col. 1, para. 2). Sugiura establishes that amount of PAPS and enzyme can vary depending on enzyme and substrate (pg. 3392, col. 2, para. 1). Liu teaches sulfate group donor PAPS is added 1.1 to 1.5 times the molar mass of the glucosamine residue contained in the intermediate (English translation, pg. 5, para. 3). This establishes that the amount of sulfation is dependent on the amount of glucosamine units.
Together, wherein the general steps of enzymatic hydrolysis and enzymatic sulfation are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation (See MPEP 2144.05 (II)). Thus it would have been prima facie obvious to optimize the relative ratios in the enzymatic reactions in order to maximize yield and enzymatic efficiency and arrive at the claimed values.
Regarding claim 8: Huckerby does not teach wherein the sulfation occurs in a buffer and is purified following the reaction.
However, Liu teaches the sulfation occurs ina buffer solution and is purified following the reaction (English translation, pg. 5, para. 7).
Taken together it would have been prima facie obvious to carry out the sulfation in a buffer and purify following the reaction as taught by Liu. A person of ordinary skill in the art would have had the motivation to do so with a reasonable expectation of success as buffers are commonly used in chemoenzymatic methods as a reaction media and purification is utilized to separate the product from the starting material.
Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over Huckerby (Eur. J. Biochem., 2001, cited on PTO-892), Volpi (Carbohydrate Polymers, 2005, cited on PTO-892), Sugiura (J. Biological Chem., 2012, cited in PTO-892), D’Ambrosio (Scientific Reports, 2020, cited on PTO-892), Xu (International Journal of Biological Macromolecules, 2019, cited on PTO-892), Wang (CN 111741963, IDS filed February 22, 2024, English translation provided on PTO-892), and Liu (CN 111154819, IDS filed February 22, 2024, English translation provided on PTO-892) as applied to claim 1 above in view of Vazquez (Marine Drugs, 2013, cited on PTO-892).
Regarding claim 6: As discussed above, Huckerby teaches the oligosaccharides, following degradation, were isolated via chromatography on a Spherisorb S5 column, column eluate was monitored at 232 nm, followed by pooling oligosaccharides and subjected to a BioGel P-2 column, then lyophilized (pg. 1182, col. 2, para. 4). D’Ambrosio teaches purification methods comprising centrifugation, precipitation, and ultrafiltration methods ranging from 30 kDA to 5 kDa (pg. 4, figure 1).
They do not teach wherein the chondroitin oligosaccharide is purified with 1 kDa ultrafiltration.
However, Vazquez teaches general steps for chondroitin sulfate recovery and purification processes including centrifugation, diafiltration steps from 10-kDa (pg. 752, figure 1). The last step of purification by membrane technologies is widely performed in the majority of the biomacromolecules downstream processing (with higher sizes of 1 kDa) because of its separation effectiveness, easy scale-up, cost effective device, numerous types and cut-off membranes and simple operatory and control (pg. 752, para. 2).
Taken together it would have been prima facie obvious to incorporate 1 kDa ultrafiltration into the purification method as suggested by Vazquez. A person of ordinary skill in the art would have had the motivation to do so with a reasonable expectation of success as the use ultrafiltration membranes ranging from 30-1 kDa are a known technique in the art of purifying chondroitin saccharides for the purpose of improving purity of the final product.
Conclusion
No claims are allowed in this action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SAMUEL L GALSTER whose telephone number is (571)270-0933. The examiner can normally be reached Monday - Friday 8:00 AM - 5:00 PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Scarlett Y Goon can be reached at 571-270-5241. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SAMUEL L GALSTER/Examiner, Art Unit 1693
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