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 .
Status
The finality of the office action mailed on 10/27/2025 is withdrawn, and the prosecution has been reopened to modify the New matter rejection. The time for reply resets from the mailing of the instant office action.
Priority
This application was filed on and is a U.S. national Stage application under 35 U.S.C. 371 of International Patent Application No. PCT/NL2019/050696 filed 10/23/2019, which claims the benefit of the priority of Netherlands Patent Application No. 2021875 filed 10/25/2018.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Claim Status
Claims 1-2, 4-6, 8-10, 12-16, 19-22 are pending. Claims 1-2, 6, and 12-13 are amended. Claims 3, 7, 11, 17-18 are canceled. Claims 19-22 are new. Claim 16 is withdrawn from consideration.
Claims 1-2, 4-6, 8-10, 12-15 and 19-22 are being examined on the merits in this office action.
Claim Objections - Withdrawn
The objection of claims 1, 12, and 13 is withdrawn in view of the claim amendments.
Claim Rejections - Withdrawn
The rejection of claims 1-2, 4-6, 8-10, and 12-15 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, is withdrawn in view of the claim amendments.
The rejection of claims 1-2, 4-6, 8-10, and 12-15 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in view of the claim amendments.
The rejection of claims 1, 4-5, 9, 12, and 14-15 under 35 U.S.C. 102(a)(1) as being anticipated by over Pronk et al. (Water Research, Volume 122, 2017, Pages 148-158) – (IDS 05/25/2021) as evidenced by Louisiana Tech is withdrawn in view of the claim amendments.
The rejection of claims 1-2,4-6, 9, 12, and 14-15 under 35 U.S.C. 102(a)(1) as being anticipated by Loosdrecht et al. (US20160230345A1 – hereinafter “Loosdrecht”) as evidenced by Louisiana Tech is withdrawn in view of the claim amendments.
The rejection of claims 8, 10 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Pronk et al. (Water Research, Volume 122, 2017, Pages 148-158) – (IDS 05/25/2021) as evidenced by Louisiana Tech, as applied to claim 1 above, and further in view of Lin et al. (WO2015190927A1 - hereinafter “Lin”) is withdrawn in view of the claim amendments.
Claim Rejections - 35 USC § 112 - New
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 1-2, 4-6, 8-10, 12-15, 19-20, and 22 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a NEW MATTER rejection.
The response filed 07/25/2025 has introduced NEW MATTER into the claims. The newly added/amended Claim(s) 1 recites “heparan”. The response did not specifically and adequately point out where support for newly added/amended Claim(s) 1 could be found in the originally filed disclosure.
Although the PTO has the initial burden of presenting evidence or reasons why persons skilled in the art would not recognize in the disclosure a description of the invention defined by the claims, when filing an amendment an applicant should show support in the original disclosure for new or amended claims. See MPEP 714.02 and 2163.06 (“Applicant should therefore specifically point out the support for any amendments made to the disclosure.”).
The amended claims now recites limitations, which were not clearly disclosed in the specification as filed, and now change the scope of the instant disclosure as filed. Such limitations recited in newly amended claim, which did not appear in the specification, as filed, introduce new concepts and violate the description requirement of the first paragraph of 35 U.S.C 112. Heparan is not found in the disclosure. Examiner notes that the instant disclosure recites that the biomedical compounds are heparan like polymer (See [0019] of the published disclosure). Examiner notes that a heparan like compound is different from heparan. Applicant is required to provide sufficient written support for the limitations recited in the present claims in the specification, or claims as-filed, or remove these limitations from the claims in response to this Office Action.
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 1-2, 4-6, 8-10, 12-15 and 19-22 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 1 recites the limitation "the biomedical compound comprises at least one disaccharide and wherein the biomedical compound is selected from at least one of a heparan or a heparin…” in line 15-16. Examiner is interpreting this to mean that the compound produced by the method step can be both heparin and heparan. However, according to the instant disclosure, it appears that one compound is being produced. It is therefore unclear exactly how many products are being produced by the recited method rendering the claim indefinite. The dependent claims 2, 4-6, 8-10, 12-15 and 19-22 do not seem to clear up the indefiniteness and are also rejected.
Claim Rejections - 35 USC § 103 - New
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1- 2, 4-6, 9, 12, 14-15, and 19-22 are rejected under 35 U.S.C. 103 as being unpatentable over Pronk et al. (Water Research, Volume 122, 2017, Pages 148-158) – (IDS 05/25/2021), in view of Vu et al. (Molecules, 2009 Jul 13; 14 (7): 2535–2554) and Vaidyanathan et al. (Bioeng. Transl. Med. 2016 Nov 21;2(1):17–30 – herein “Vai”).
Pronk teaches an acid soluble extracellular polymeric substance (acid soluble EPS) was extracted from an acetate fed aerobic granular sludge reactor and that the experiments were conducted in a sequencing batch reactor (SBR) fed with acetate as the sole carbon source (Section 2.1). Pronk teaches that the acid soluble EPS is α-(1 → 4) linked polysaccharide, containing both glucose and galactose as monomers (Abstract). Pronk teaches both aerobic (Abstract; introduction) and anaerobic conditions (Section 2.1). Pronk teaches that the abundant microbial species was most likely, Defluviicoccus Cluster II related (Section 3.2) which is a known glycogen accumulating organism (GAO). Pronk teaches that the glycoproteins containing EPS were isolated from the granular sludge (Section 4.1, 2nd paragraph). Pronk teaches microorganisms including Alphaproteobacteria (Section 2.1; Section 3.2) which belongs to the instant Proteobacteria and further teaches bacteria including beta and gamma proteobacteria (See Fig. 3).
Pronk does not teach wherein the biomedical compound is heparan or heparin.
However, the use of the instant bacteria to produce biomedical compounds such as heparan or heparin is known in the art as taught by Vu et al. Vu teaches EPS produced by microorganisms are a complex mixture of biopolymers primarily consisting of polysaccharides, as well as proteins, nucleic acids, lipids and humic substances (Abstract). Vu teaches the use of gammaproteobacterial to produce polysaccharides such as N-acetylheparosan (which is a type of heparan polymer), alginate and xanthan, and that some microorganism polysaccharides that have the same structure as heparin, as the non-sulfated precursor polysaccharide in heparin biosynthesis (a type of heparan-like or heparin polymer (Section 9.2.3). Vu teaches that gram positive bacteria including Alphaproteobacteria, Betaproteobacteria and Gammaproteobacteria produce extracellular polysaccharides where polymers are generally composed of D-glucose, or heteropolysaccharides, where the repeating units range from disaccharides to octasaccharides with unusual side chains (section 9.2). Vu teaches that the use of bacterial polysaccharides as sources of heparin synthesis may eliminate concerns associated with mammalian sources of heparin, and also be useful in medical research (Page 2545, 2nd paragraph).
Further Vai teaches bacterial biosynthesis of heparosan (section 2.1.2) and that some bacterial strains can be used to synthesize polysaccharides such as heparin, HA, and CS (see section 3.1) and that heparin contains repeating disaccharide units containing 2‐O‐sulfo‐α‐L‐iduronic acid (IdoA2S) 1,4‐linked to 6‐O‐sulfo‐N‐sulfo‐α‐D‐glucosamine (section 1.1). Vai teaches that the heparin can be prepared to have low molecular weight of 4-6kda (section 1.1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method taught by Pronk to produce other polysaccharides such as heparin or heparan since Vu teaches similar bacteria are used to produce heparin and heparan polymers (see page 2545) and Vai teaches the use of bacterial strains to produce polysaccharides such as heparin. One of ordinary skill in the art would be motivated and would have had a reasonable expectation of success in using the method of Pronk to produce polysaccharides such as heparin and heparan since Vu teaches similar bacteria to produce heparin and heparan polymers thus proving other sources of heparin synthesis. The disclosures render obvious claim 1.
Regarding claims 2, and 6, Vai teaches that the heparin can be prepared to have low molecular weight of 4-6kda (section 1.1). It would have been obvious to modify the method of Pronk to produce low molecular weight heparin so as to have improved bioavailability and pharmacodynamics making them better than heparin for certain therapeutic applications (See section 1.1).
Regarding claim 4, Pronk teaches that the granules are dominated by Defluviicoccus cluster II organisms (Abstract).
Regarding claim 5, Pronk teaches that aerobic granular sludge is comprised out of several microbial layers from the core to the fringe (Section 3.1; also Fig. 1 description). Pronk teaches that the EPS dominated granules exhibited a remarkable and distinctive tangled tubular morphology (See Abstract).
Regarding claim 9, Pronk teaches the microorganism grown in a reactor fed with acetate as the sole carbon source at 35 °C, that the feed consists out of 1200 mL of water at 39 °C and 150 mL of N-source and 150 mL of C-source, that the concentrated C-source medium contained 92 g of sodium acetate per 10 L of demi water. The concentrated N-source medium contained per 10 L of demi water; 11.26 g NH4Cl, 1.25 g K2HPO4, 0.5 g KH2PO4, 8.8 g MgSO4·7H2O, 3.5 g KCl and 90 g trace element solution (Section 2.1).
Regarding claim 12, Pronk teaches an acid soluble extracellular polymeric substance (acid soluble EPS) was extracted from an acetate fed aerobic granular sludge reactor and that the experiments were conducted in a sequencing batch reactor (SBR) fed with acetate as the sole carbon source (Section 2.1).
Regarding claims 14-15, Pronk teaches 3.9% of soluble EPS could be extracted (Section 3.3, last paragraph). Pronk further teaches that the acid soluble EPS is α-(1 → 4) linked polysaccharide, containing both glucose and galactose as monomers (Section 3.4, last paragraph). Further, Examiner notes that all the steps of the recited method are taught by Pronk and Vu teaches suing the instant bacteria to produce heparin-like and heparan compounds. Thus the wherein clause in claims 14-15 is not given weight when it simply expresses the intended result of a process step positively recited (See MPEP 2111.04).
Regarding claim 19-20, Vu teaches the use of gammaproteobacterial to produce polysaccharides such as N-acetylheparosan, which is a type of heparan polymer (Section 9.2.3). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method taught by Pronk to produce other biomedical compounds such as heparan since Vu teaches similar bacteria to produce heparan polymers (see page 2545).
Regarding claim 21-22, Vu teaches the use of gammaproteobacterial to produce polysaccharides such as N-acetylheparosan and polysaccharides that have the same structure as heparin, as the non-sulfated precursor polysaccharide in heparin biosynthesis (a type of heparan-like or heparin polymer (Section 9.2.3). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method taught by Pronk to produce other biomedical compounds such as heparin since Vu teaches similar bacteria to produce heparin polymers (see page 2545).
Claims 8, 10, and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Pronk et al. (Water Research, Volume 122, 2017, Pages 148-158) – (IDS 05/25/2021), in view of Vu et al. (Molecules, 2009 Jul 13; 14 (7): 2535–2554) and Vaidyanathan et al. (Bioeng. Transl. Med. 2016 Nov 21;2(1):17–30 – herein “Vai”), as applied to claim 1 above, and further in view of Lin et al. (WO2015190927 - hereinafter “Lin”).
The teachings of Pronk, Vu and Vai are disclosed above and incorporated herein by reference.
Pronk does not teach the supplements such as sugars, fatty acids, proteins, and minerals as recited in claim 8.
Lin teaches extraction of a biopolymer from a granular sludge (Abstract), that the biopolymers are from dense aggregates formed by microbial organisms, comprising the steps of
(i) providing an anionic biopolymer in sludge, (ii) increasing the pH to 8.0-14.0 under addition of at least 1-20 % v/v of at least one of Cl2, 0C1- and H202, at a suitable temperature and during a suitable time, and (iii) extracting the biopolymer (claim 1). Lin teaches that the polysaccharide is obtained by the aerobic cultivation of a bacterium of the species Azotobacter vinelandii in an aqueous nutrient medium containing sources of carbon, molybdenum, iron, magnesium, potassium, sodium, sulfate, calcium and phosphate and that the carbon source comprises at least one monosaccharide or disaccharide, that the phosphate concentration in the nutrient medium is 0.1-0.8 millimolar, and the pH of the medium is maintained within the range of from 7.0 to 8.2 (Page 2, line 32-40). Lin teaches that Extracellular polymeric substances obtainable from granular sludge (preferably obtained from granular sludge) do not require further purification or treatment to be used for some applications, hence can be applied directly (Page 2, line 5-8) and that the extracellular polymeric substances, in particular linear polysaccharides, obtainable from granular sludge can be produced in large quantities (Page 1, line 18-21). Lin teaches that the polysaccharide is obtained by the aerobic cultivation of a bacterium of the species Azotobacter vinelandii in an aqueous nutrient medium containing sources of carbon, molybdenum, iron, magnesium, potassium, sodium, sulfate, calcium and phosphate (Page 2, line 32-35) which are examples of minerals.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Pronk with the teachings of Lin and supply the supplements such as carbon, molybdenum, iron, magnesium, potassium, sodium, sulfate, calcium and phosphate since Lin teaches that such extracellular polymeric substances, in particular linear polysaccharides, obtainable from granular sludge can be produced in large quantities (Page 1, line 18-21). One of ordinary skill in the art would be motivated and would have had a reasonable expectation of success in modifying the method of Pronk with the teachings of Lin since both reference teach isolating biomedical substances using microorganisms and Lin teaches that Extracellular polymeric substances obtainable from granular sludge (preferably obtained from granular sludge) do not require further purification or treatment to be used for some applications, hence can be applied directly (Page 2, line 5-8). The disclosures render obvious claim 8.
Regarding claim 10, Pronk teaches sequencing batch reactor (SBR) fed with acetate as the sole carbon source at 35 °C. The settling time was gradually decreased from 15 to 3 min over the course of two weeks and was maintained for the duration of the experiment (6 months), that the 3-h cycle starts with a plug flow feed period of 1 h of anaerobic feeding at 1500 mL h−1 from the bottom of the reactor. The feed consists out of 1200 mL of water at 39 °C and 150 mL of N-source and 150 mL of C-source both at room temperature as to result in a final influent temperature of 35 °C. Feeding is followed by a 112-min aeration period, a settling period of 3 min, and a 5 min effluent period in which the total volume in the reactor is brought back to 1.24 L. The reactor is kept at 35 °C throughout the whole cycle and the dissolved oxygen in the aeration period is set at 60% (3.4 mgO2 L−1). The pH is controlled between 7.1 and 6.9 by 1 M solutions of HCl and NaOH respectively. Solid retention time is kept at approximately 20 days, that the concentrated C-source medium contained 92 g of sodium acetate per 10 L of demi water and that the concentrated N-source medium contained per 10 L of demi water; 11.26 g NH4Cl, 1.25 g K2HPO4, 0.5 g KH2PO4, 8.8 g MgSO4·7H2O, 3.5 g KCl and 90 g trace element solution (whole section 2.1). Pronk teaches the oxygen concentration but does not teach the recited concentration of 200-500mg/l. Examiner notes that one of ordinary skill in the art would be motivated through routine experimentation to optimize the oxygen concentrations of the excipients taught by both Pronk to arrive at the concentrations of the instant claims. See MPEP 2144 (II).
Regarding claim 13, Pronk teaches the extracellular polymer granules were collected from the lab-scale reactor. Fresh granules (1 g in dry weight) were added into 100 mL 0.5% (w/v) Na2CO3 solution and heated for 30 min at 80 °C. After centrifugation, the supernatant was used for the ALE extraction, and the pellet was used to extract the acid soluble EPS. The solution was then stirred and heated in a water bath at 95 °C for 20 h. Then the suspension was centrifuged for 20 min. The supernatant was collected and filtered through 0.2 μm filter. Then ethanol (98%, 1:1 vol) was added to the supernatant. The precipitate was lyophilized and named “acid soluble extracellular polymeric substance” (acid soluble EPS) (section 2.4). Further, Lin teaches the method comprising increasing the pH to 8.0-14.0, removing particles with a diameter larger than 500pm (this reads on removing insoluble substances), reducing the pH, by addition of an acid, removing the sludge by one or more of physical separation, settling, centrifugation, cyclonic separation, decantation, filtration, sieving, and flotation, under suitable conditions (claims 1-5). Lin further teaches that the method comprises the step of addition of a salt comprising a base, and an oxidant, temperature is increased to 50-100°C for a period of 10-60 min (Claims 8-9). Lin further teaches that the extraction is preferably carried out under mixing, such as by stirring (Page 3, line 17-19). It would have been obvious to modify Pronk with the teachings of Lin and increase the pH of the mixture so as to extract the extracellular polymeric substances, since both reference teach isolating biomedical substances using microorganisms.
Response to Arguments
Applicant’s arguments, see Applicant arguments, filed 07/25/2025, with respect to the rejection(s) of claim(s) 1-2, 4-6, 8-10, 12-15 under 112, 102, and 103 have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of Vu and Vai et al.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Mercy H. Sabila whose telephone number is (571)272-2562. The examiner can normally be reached Monday - Friday 5:00 am - 3:00 pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Lianko G. Garyu can be reached at (571)270-7367. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/MERCY H SABILA/Examiner, Art Unit 1654
/LIANKO G GARYU/Supervisory Patent Examiner, Art Unit 1654