The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
This office action is in response to Applicants’ amendments/remarks received August 8, 2026.
Rejections and/or objections not reiterated from previous office actions are hereby withdrawn.
Claims 9-11, 14-16 are canceled. Claims 1-8, 12-13, 17, 18-27 are under consideration.
Priority: This application is a 371 of PCT/EP2022/087724, filed December 23, 2022, which claims benefit to foreign applications EP 21217519.4, filed December 23, 2021, and EP 22205881.0, filed November 7, 2022. Copies of the foreign priority documents have been received in the instant application on June 21, 2024, and are in the English language.
Objections and Rejections
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 13, 17 are rejected under 35 U.S.C. 101 because the claimed invention is not directed to patent eligible subject matter. The instant claims are product claims reciting microbial fermentation products that are not markedly different from natural biomolecules.
Claims 13, 17 recite a microbial fermentation product comprising less than 10 ng/g of recombinant DNA. Claim 13 further the microbial fermentation product comprises a fungal DNase and at least 0.1% w/w of a recombinant protein of interest. The patentability of a product does not depend on its method of production, i.e. a product-by-process is not limited to manipulation of the recited steps but instead is limited to the structure implied by the steps. MPEP 2113. The limitation “recombinant” is a process by which the protein is interest is produced. The claims recite enzymes (fungal DNase) and/or proteins comprising amino acid sequences that are the same as naturally occurring enzymes and proteins. The claims are directed to a statutory category, i.e. a composition of matter (step 1: YES).
Since the claims recite a nature-based product, i.e. any microbial fermentation product, any protein, or a fungal DNase, the claims are analyzed to determine whether it is directed to any judicial exception. The markedly different characteristics analysis is performed by comparing the nature-based product limitation in the claim to its naturally occurring counterpart to determine if it has markedly different characteristics from the counterpart. The recited fermentation product, recombinant protein, and fungal DNase are compared to its closest naturally occurring counterpart(s) to determine if it has markedly different characteristics. Here, the closest natural counter parts are any naturally occurring biomolecule or protein and naturally occurring fungal DNase. When the claimed product/protein and fungal DNase are compared to these counterparts, the comparison indicates that there are no differences in structure, function, or other characteristics. Microbial products, including proteins and fungal DNases, are naturally occurring and found in nature. There is no indication that the claimed product/protein and fungal DNase have any structural and/or functional characteristics that are different from the naturally occurring protein and DNase in their natural state. Therefore, the microbial product, recombinant protein, and fungal DNase do not have markedly different characteristics from what occurs in nature and is a "product of nature" exception. Accordingly, the claims are directed to an exception (step 2A: YES). Next, the claims as a whole are analyzed to determine whether any additional element, or combination of elements, is sufficient to ensure that the claim amounts to significantly more than the exception(s). Claim 13 recites the microbial product comprises less than 10 ng/g of recombinant DNA and at least 0.1% w/w of a recombinant protein of interest. As noted above, the limitation “recombinant” is a process by which the protein is interest is produced; therefore, the claim recites enzymes (fungal DNase) and/or proteins comprising amino acid sequences that are the same as naturally occurring enzymes and proteins. There is no indication that the product (protein, fungal DNase) separated from DNA and in a more purified state has any characteristics (structural, functional, or otherwise) that are different from naturally occurring proteins and fungal DNase. Claim 17 is drawn to any microbial fermentation product, which encompasses any naturally occurring biomolecule. The products do not comprise any additional components. The claims do not recite anything significantly different than the natural products, i.e. the claims do not recite elements or features that demonstrate that the claimed products, proteins, and DNase are markedly different from what exists in nature. Therefore, the claims as a whole add nothing significantly more to the "product of nature" itself (Step 2B: NO), and thus, the claims do not qualify as eligible subject matter.
See also Funk Brothers Seed Co., V. Kalo Inoculant Co., 333 U.S. 127, (1948) and Association for Molecular Pathology v. Myriad Genetics, Inc. 569 U.S., 133 S. Ct. 2107, 2116, 106 USPQ 2d. 1972 (2013).
Reply: Applicants’ amendments/remarks have been considered but they are not persuasive. Claims 13, 17 remain rejected under 35 U.S.C. 101 for the reasons noted.
Applicants assert claim 13 has been amended to require a specific combination that does not exist in nature (a) a fungal DNase or variant thereof that is a NUC nuclease; (b) at least 0.1% w/w of a recombinant protein of interest; and less than 10 ng/g of recombinant DNA. Applicants assert that the low residual-DNA limitation is not a mere purification or isolation of a natural molecule; it is the result of a non-natural processes that degrades recombinant host DNA to levels unattainable by natural processes or by the prior-art methods.
Applicants’ remarks are not persuasive. Firstly, it is noted that claim 13 is a product claim drawn to a microbial fermentation product comprising a fungal DNase and at least 0.1% w/w of a recombinant protein of interest. Claim 13 is not drawn to a method claim. Additionally, as noted above, the patentability of a product does not depend on its method of production, i.e. a product-by-process is not limited to manipulation of the recited steps but instead is limited to the structure implied by the steps. MPEP 2113. The limitation “recombinant” is a process by which the protein is interest is produced. Therefore, the claims recite enzymes (fungal DNase) and/or proteins comprising amino acid sequences that are the same as naturally occurring enzymes and proteins.
The recited fermentation product, recombinant protein, and fungal DNase are compared to its closest naturally occurring counterpart(s) to determine if it has markedly different characteristics. Here, the closest natural counter parts are any naturally occurring biomolecule or protein and naturally occurring fungal DNase. When the claimed product/protein and fungal DNase are compared to these counterparts, the comparison indicates that there are no differences in structure, function, or other characteristics. Microbial products, including proteins and fungal DNases, are naturally occurring and found in nature. There is no indication that the claimed product/protein and fungal DNase have any structural and/or functional characteristics that are different from the naturally occurring protein and DNase in their natural state. Therefore, the microbial product, recombinant protein, and fungal DNase do not have markedly different characteristics from what occurs in nature and is a "product of nature" exception. Accordingly, the claims are directed to an exception (step 2A: YES). Claim 13 recites the microbial product comprises less than 10 ng/g of recombinant DNA and at least 0.1% w/w of a recombinant protein of interest. As noted above, the claim recites enzymes (fungal DNase) and/or proteins comprising amino acid sequences that are the same as naturally occurring enzymes and proteins. There is no indication that the product (protein, fungal DNase) separated from DNA and in a more purified state has any characteristics (structural, functional, or otherwise) that are different from naturally occurring proteins and fungal DNase.
Regarding instant claim 17, as also noted by Applicants, claim 17 is a product-by-process claim. However, claim 17 is drawn to any microbial fermentation product, which encompasses any naturally occurring biomolecule.
Claims 13, 17 do not recite anything significantly different than the natural products, i.e. the claims do not recite elements or features that demonstrate that the claimed products, proteins, and DNase are markedly different from what exists in nature. Therefore, the claims as a whole add nothing significantly more to the "product of nature" itself (Step 2B: NO), and thus, the claims do not qualify as eligible subject matter.
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.
Claims 1-6, 8, 12-13, 17, 18-27 are rejected under 35 U.S.C. 103 as being unpatentable over Kaya et al. (EP 3926039; IDS 06.21.24, previously cited) and Gori et al. (WO 2015155350; previously cited). Kaya et al. disclose that an increase in the viscosity of a fermentation broth is at least partly ascribed to larger amounts of nucleic acids in the fermentation broth (at least paragraph 0007) and that the increase in viscosity is due to an interaction of DNA and cells and not only due to the presence of DNA (at least paragraph 0040). Kaya et al. disclose it has been surprising found that directly adding a nuclease to the fermentation broth effected by a filamentous fungus or a Bacillus, no further increase in viscosity is observed (at least paragraph 0039). Kaya et al. disclose a method comprising cultivating a microorganism capable of producing a target product, obtaining a fermentation broth comprising the microorganism and target product, adding a nuclease to the fermentation broth, and recovering the microorganism or the target product, where the end of the fermentation process includes a flocculation step and several filtration steps, where the filter medium has a size greater than 0.5 µm (at least p. 6 paragraphs 0035-0036), where the nuclease is a DNase (at least paragraph 0020), where the target product is any protein of interest (at least paragraph 0042). Kaya et al. disclose that the DNase can be obtained from a number of sources and may be bacterial nucleases or fungal nucleases (at least paragraph 0020). Kaya et al. disclose a preferred nuclease is from a filamentous fungus, preferably from Aspergillus oryzae (at least paragraph 0022). Kaya et al. do not explicitly teach the amino acid sequence of Aspergillus oryzae (instant SEQ ID NO: 2).
Gori et al. disclose Aspergillus oryzae DNase polypeptides have DNase activity and are stable in compositions (at least p. 13-14). Gori et al. disclose it has been surprisingly found that formulating DNase obtained from a fungal source is more stable than the bacterial DNase obtained from a bacterial source (p. 13). Gori et al. disclose that the polypeptide having DNase activity can be obtained from Aspergillus, for example from Aspergillus oryzae (p. 13). Gori et al. disclose the Aspergillus oryzae DNase polypeptide comprises the amino acid sequence of SEQ ID NO: 2 (p. 22, 45), which has 100% sequence identity with instant SEQ ID NO: 2.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the references and arrive at the claimed method for reducing DNA in a microbial fermentation product, comprising providing a fermentation broth comprising microbial host cells, recombinant DNA from the microbial host cells, and protein of interest produced by the microbial host cells; adding a nuclease (DNase) to the fermentation broth; subjecting the fermentation broth to a flocculation step; subjecting the fermentation broth supernatant to a membrane filtration step where the membrane filter has a size less than 100 kDa; wherein the microbial host cells are Bacillus bacterial cells; and wherein the DNase is a Aspergillus oryzae DNase polypeptide (instant claims 1, 8, 18, 20-22). The motivation to do so is given by the prior art. Kaya et al. disclose it has been surprising found that directly adding a nuclease to the fermentation broth effected by a filamentous fungus or a Bacillus, no further increase in viscosity is observed. Kaya et al. disclose a method comprising cultivating a microorganism capable of producing a target product, obtaining a fermentation broth comprising the microorganism and target product, adding a nuclease to the fermentation broth, and recovering the microorganism or the target product, where the end of the fermentation process includes a flocculation step and several filtration steps, where the filter medium has a size greater than 0.5 µm, where the DNase is a fungal DNase, preferably from Aspergillus oryzae. Gori et al. disclose the amino acid sequence of Aspergillus oryzae DNase polypeptide (SEQ ID NO: 2). Gori et al. disclose formulating DNase obtained from a fungal source is more stable than the bacterial DNase obtained from a bacterial source. Therefore, one of ordinary skill would have reasonable motivation to incorporate the Aspergillus oryzae DNase polypeptide (SEQ ID NO: 2) of Gori et al. for the DNase added to the fermentation broth in the method comprising cultivating a Bacillus microorganism capable of producing a target product of Kaya et al. noted above. One of ordinary skill would have a reasonable expectation of success because the prior art disclose that the DNase for reducing viscosity in the fermentation broth may be fungal (Kaya et al.) and the prior art discloses that the fungal cell Aspergillus oryzae expresses DNase, specifically the polypeptide comprising the amino acid sequence of instant SEQ ID NO: 2 (Gori et al.).
Regarding instant claims 5-6, Kaya et al. disclose that the filtration technique is ultrafiltration and/or microfiltration (at least paragraph 0018).
Regarding instant claims 2, 4, 24, 27, Kaya et al. disclose the target product includes enzymes produced by recombinant modification of the microorganism (at least paragraphs 0012, 0042).
Regarding instant claims 3, 12-13, 17, 19, 23, 25, 26, since Kaya et al. in view of Gori et al. reasonably disclose a method comprising the same combination of steps and materials recited and for the same purpose of reducing viscosity, and thereby DNA content, Kaya et al. in view of Gori et al. can be deemed to disclose the fermentation broth after treatment with the DNase, comprises essentially no DNA and an amount of the protein of interest of at least 1% w/w.
Reply: In view of Applicants’ amendments/remarks, the previous 102(a)(1) rejections as being anticipated by Hobel et al., Hoffmann et al., and Kaya et al. have been withdrawn. However, the claims are unpatentable under a new 103 rejection over Kaya et al. in view of Gori et al. for the reasons noted above.
Applicants assert that Kaya et al. teaches addition of a nuclease (preferably bacterial NucB) to a fermentation broth containing intact cells to reduce or prevent an increase in viscosity. Applicants assert that nor does Kaya et al. teach the combination of a specific fungal DNase with a bacterial host cell selected from the claimed group, flocculation/precipitation, and membrane filtration having a size-exclusion limit of less than 100 kDa or less than 1 µm, resulting in a product containing less than 10 ng/g recombinant DNA.
Applicants’ remarks are not persuasive. MPEP 2123 notes that “[t]he prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed….” In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004). In this instance, Kaya et al. disclose that the DNase can be obtained from a number of sources and may be bacterial nucleases or fungal nucleases (at least paragraph 0020). Kaya et al. disclose a preferred nuclease is from a filamentous fungus, preferably from Aspergillus oryzae (at least paragraph 0022). Kaya et al. disclose it has been surprising found that directly adding a nuclease to the fermentation broth effected by a filamentous fungus or a Bacillus, no further increase in viscosity is observed (at least paragraph 0039). Therefore, Kaya et al. fairly disclose the combination of a specific fungal DNase with a bacterial host cell selected from the claimed group, i.e. Bacillus.
As noted above, Kaya et al. further disclose recovering the microorganism or the target product, where the end of the fermentation process includes a flocculation step and several filtration steps, where the filter medium has a size greater than 0.5 µm (at least p. 6 paragraphs 0035-0036), where the target product is any protein of interest (at least paragraph 0042).
Therefore, since Kaya et al. reasonably disclose the recited combination of a specific fungal DNase (Aspergillus oryzae DNase) with a bacterial host cell selected from the claimed group (i.e. Bacillus), flocculation/precipitation, and membrane filtration having a size less than 100 kDa, it would follow that the resulting fermentation broth contains essentially no DNA or less than the recited 10 ng/g recombinant DNA.
Kaya et al. differ from the claimed method by not explicitly teaching the amino acid sequence of Aspergillus oryzae DNase.
However, as noted above, Gori et al. disclose the Aspergillus oryzae DNase polypeptide comprises the amino acid sequence of SEQ ID NO: 2 (p. 22, 45), which has 100% sequence identity with instant SEQ ID NO: 2.
Therefore, it would have been obvious to incorporate the Aspergillus oryzae DNase polypeptide (SEQ ID NO: 2) of Gori et al. for the DNase added to the fermentation broth in the method comprising cultivating a Bacillus microorganism capable of producing a target product of Kaya et al. noted above. One of ordinary skill would have a reasonable expectation of success because the prior art disclose that the DNase for reducing viscosity in the fermentation broth may be fungal (Kaya et al.) and the prior art discloses that the fungal cell Aspergillus oryzae expresses DNase, specifically the polypeptide comprising the amino acid sequence of instant SEQ ID NO: 2 (Gori et al.).
Applicants assert that Gori et al. is directed to detergent and pharmaceutical compositions containing fungal DNase for laundry and biofilm applications. Applicants assert that Gori et al. contain no teaching of residual-DNA reduction in microbial fermentation products, no teaching of bacterial production hosts, and no teaching of the recovery process (flocculation + defined membrane filtration) required by claim 1.
Applicants’ remarks are not persuasive. In this instance, Gori et al. is cited as a 103 reference with Kaya et al. As noted above, Kaya et al. disclose that the DNase added to a fermentation broth for reducing viscosity and/or DNA can be obtained from a number of sources and may be bacterial nucleases or fungal nucleases (at least paragraph 0020). Kaya et al. disclose a preferred nuclease is from a filamentous fungus, preferably from Aspergillus oryzae (at least paragraph 0022). Therefore, Kaya et al. disclose that the Aspergillus oryzae DNase polypeptide comprising the amino acid sequence of SEQ ID NO: 2 of Gori et al. has utility in a fermentation broth for reducing viscosity and/or DNA. Additionally, since Gori et al. is cited with Kaya et al., the deficiencies of Gori et al. to not teach residual-DNA reduction in microbial fermentation products, bacterial production hosts, and a recovery process (flocculation + defined membrane filtration) are remedied by Kaya et al. See the teachings of Kaya et al. noted above.
Applicants assert that a person of ordinary skill would have no reasonable expectation of success. Applicants assert that the specification demonstrates that bacterial nucleases are ineffective at reducing residual DNA in enzyme concentrates derived from Bacillus fermentations, whereas the claimed fungal (NUC3) DNase is highly effective under the same conditions (examples 2-4, 7-9). Applicants assert that nothing in Gori et al. would have predicted this differential efficacy.
Applicants’ remarks are not persuasive. Gori et al. has already disclosed that fungal DNase obtained from a fungal source is more stable than bacterial DNase obtained from a bacterial source (p. 13). Therefore, it would be obvious and expected that the fungal DNase disclosed in Kaya et al. or Gori et al. is highly effective over bacterial DNase in a fermentation broth composition.
Claims 1-6, 7, 8, 12-13, 17, 18-27 are rejected under 35 U.S.C. 103 as being unpatentable over Kaya et al. (EP 3926039; IDS 06.21.24, previously cited) and Gori et al. (WO 2015155350; previously cited) and Schönert et al. (WO 2018210794; IDS 08.10.26). The teachings of Kaya et al. and Gori et al. over at least instant claims 1-6, 8, 12-13, 17, 18-27 are noted above.
Regarding instant claim 7, Schönert et al. disclose that some target enzymes cannot be secreted and need to be expressed as an intracellular enzyme; to release them from the expression host a cell disruption step is needed (at least paragraph 0005). Schönert et al. disclose Figure 1 shows a scheme of the process for manufacture of enzyme products, including fermentation of bacterial cells, homogenization/disruption step of the recombinant bacterial cells, nuclease treatment, solid/liquid separation, (micro)-filtration (at least paragraph 0013, also Figure 1). Schönert et al. disclose that surprisingly it has been shown that the combination of the three process steps leads to the desired reduction of recombinant DNA: treatment with a nuclease (i.e. a nuclease enzyme) to hydrolyze DNA; use of a precipitation agent and/or flocculant to precipitate hydrolyzed DNA through the formation of insoluble complexes; and conduction of a subsequent microfiltration step (at least paragraph 0014). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to incorporate an intracellular protein for the target product and a homogenization/disruption step of the recombinant bacterial cells expressing the target product as suggested in Schönert et al. in the method for cultivating a bacterial microorganism capable of producing a target product comprising of Kaya et al. in view of Gori et al. noted above, comprising fermentation of Bacillus cells expressing the target product, nuclease treatment with Aspergillus oryzae DNase, solid/liquid separation by flocculation, filtration where the membrane filter has a size less than 100 kDa. One of ordinary skill would have a reasonable expectation of success because the prior art disclose target products, including intracellular proteins, can also be produced by cell disruption and nuclease treatment.
Reply: The reasons for maintaining Kaya et al. and Gori et al. are the same as noted above.
No claim is allowed.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Marsha Tsay whose telephone number is (571)272-2938. The examiner can normally be reached M-F.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Manjunath N. Rao can be reached at 571-272-0939. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/Marsha Tsay/Primary Examiner, Art Unit 1656
Prosecution Insights