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 Status
The preliminary claims amendment filed 12/07/2023 is entered. Claims 1-9, 13-14 are pending and under examination. Claims 10-12 are cancelled.
Priority
Acknowledgment is made of applicant's claim for foreign priority. However, the foreign priority document is not translated to English; therefore, the examiner cannot determine if it discloses the presently claimed invention. Therefore, the effective filing date is 06/29/2022, which is the PCT filing date.
Claim Rejections - 35 USC § 112
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 2-4 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.
Regarding claim 2, the structure is unclear regarding “a domain showing at least 80% amino acid sequence homology to each of the domains of wild-type flagellin”. Is this option directed to having “a” domain, meaning one domain, selected from sequences having at least 80% amino acid sequence homology to the wildtype counterpart domain? Or is this option directed to having all the domains where each of the domain has at least 80% amino acid sequence homology to its wildtype counterpart? What if the wildtype counterpart does not have the domains to be deleted? Secondly, are there only two options to select from, where the first option is the list of wildtype domains 0, 1, 2, and 3, so that the fragment needs to include wildtype domains 0, 1, 2, and 3; and the second option is the domain showing at least 80% amino acid sequence homology to each of the domains of wild-type flagellin? Or is each domain its own option, so that a variant could have a sequence with some wildtype domains and some domains with at least 80% sequence homology? Can a fragment not have one or more of domains 0, 1, 2, and 3?
Regarding claims 3-4, for microorganisms with flagellin that lack the domains to be deleted in claim 1, is the flagellin used as is without any further modification? Should only the microorganisms that have the domains to be deleted to start with, as claimed in claim 2, be selected?
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 1-4, 7-9 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a product of nature without significantly more. The claims recite naturally occurring flagellin protein, which is a product of nature, which are judicial exceptions to eligible statutory classes. This judicial exception is not integrated into a practical application and the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception for reasons that follow.
When a law of nature or natural phenomenon is claimed as a physical product, the courts have often referred to the judicial exception as a "product of nature". The Office’s eligibility analysis uses the term “product of nature” to refer to a "law of nature" or "natural phenomenon” claimed as a physical product. For example, see Myriad Genetics, Inc., 569 U.S. at 590-91, 106 USPQ2d at 1979 (claims to isolated DNA held ineligible because they “claim naturally occurring phenomena” and are “squarely within the law of nature exception”); Funk Bros. Seed Co. v. Kalo Inoculant Co., 333 U.S. 127, 130, 76 USPQ 280, 281 (1948) (claims to bacterial mixtures held ineligible as “manifestations of laws of nature” and “phenomena of nature”). As explained in those decisions, products of nature are considered to be an exception to the statutory classes because they tie up the use of naturally occurring things, and they have been labeled as both laws of nature and natural phenomena.
Step 1: Is the claim directed to a process machine, manufacture, or composition of matter?
Claims 1-4 and 7-9 recite a flagellin variant, the flagellin variant, or a vaccine composition comprising of the flagellin variant. Claims 3 and 4 specifically recite a flagellin variant wherein the flagellin is derived from microorganisms listed by genus and/or species. Thus, the claimed invention is directed to a process, machine, manufacturer or composition of matter.
Step 2A, Prong 1: Does the claim recite an abstract idea, law of nature, or natural phenomenon?
Claim 1 recites a flagellin variant in which N-terminal domain 2, domain 3, and C-terminal domain 2; or the amino acid sequence of SEQ ID NO: 1 is deleted in flagellin or a fragment thereof. The specification teaches that SEQ ID NO:1 is a B cell epitope found in the hypervariable region of FlaB of Vibrio vulnificus. The flagellin variant of claim 1 as stated does not exclude starting flagellin that do not contain both N-terminal domain 2, domain 3, and C-terminal domain 2 and SEQ ID NO: 1. For example, the Bacillus subtilis flagellin protein, Hag, only has domain 0 and 1 and does not have any domain 2 or domain 3, and also does not have SEQ ID NO: 1 as SEQ ID NO:1 is within domain 2 and domain 3 (US20250263450A1, Filed 10/20/2021, Published 08/21/2025, Flagellin fusion protein and use thereof; hereafter referred to as Cho. Paragraph 8). The only other flagellin gene in Bacillus subtilis, the yvzB gene has no known function, is likely a pseudogene, and would produce only a partial C-terminal domain, which would also not encompass the domains claimed to be deleted (Mukherjee, S. et al, The structure and regulation of flagella in Bacillus subtilis, Annual Review Genetics. 48:319-340, published 11/2014; hereafter referred to as Mukherjee et al. see section Filament, paragraph 1). As such, a deletion of the domains and sequences in claim 1 from flagellin derived from microorganisms that do not have flagellin with these domains and sequences would result in a flagellin variant that has the same sequence as the wildtype flagellin sequence. Therefore, claim 1 is directed to a product of nature.
Claims 2-9 and 13-14 depend on claim 1 and incorporate all its limitations.
Claim 2 recites the flagellin variant of claim 1 wherein the fragment includes a domain showing at least 80% amino acid sequence homology to each domain of the wild-type flagellin. The flagellin variant of claim 2 as stated does not exclude starting flagellin fragment that do not contain both N-terminal domain 2, domain 3, and C-terminal domain 2 and SEQ ID NO: 1. Accordingly, claims 3 and 4 do not eliminate the products of nature in claim 1.
Claims 3 and 4 recite the flagellin variant of claim 1, wherein the fragment is derived from a list of microorganisms, by genus and by species, respectively. Many Gram-positive bacteria across different genus, such as Bacillus subtilis and Clostridium difficile, express flagellin deficient in the hypervariable region, and thus contain the minimum regions (D0 and D1 regions) required for TLR5 activation and flagellin polymerization (Cho, Paragraph 9). Flagellin C from Campylobacter jejuni similarly does not have domain 2 and domain 3 regions (Faber, E., et al, Novel Immunomodulatory Flagellin-Like Protein FlaC in Campylobacter jejuni and Other Campylobacterales, mSphere 1(1):00028-15, published 12/02/2015; hereafter referred to as Faber et al. See page 13, paragraph 2). The list of microorganisms in claims 3 and 4 contain genera and species directed to these bacteria lacking the hypervariable region. Accordingly, claims 3 and 4 do not eliminate the products of nature in claim 1.
Claim 7-9 is directed to the flagellin variant retaining TLR5 stimulatory activity, inducing no flagellin-specific immune response, and has an immune boosting effect. The wildtype Hag flagellin possess these features (Cote-Cyr, M. et al. Recombinant Bacillus subtilis flagellin Hag is a potent immunostimulant with reduced proinflammatory properties compared to Salmonella enterica serovar Typhimurium FljB, Vaccine 40 (2022) 11-17, published 11/26/2021; hereafter referred to as Cote-Cyr et al. See Abstract). Therefore, these functional limitations do not exclude wildtype flagellin. Accordingly, claims 7-9 do not eliminate the products of nature in claim 1.
Therefore, claims 2-4, 7-9 are also directed to a product of nature, as they not do not eliminate the products of nature in claim 1.
Claims 1-4, 7-9 recite and are directed to patent-ineligible concepts of “product of nature”. See MPEP § 2106.04(b).
Claims 5 and 6 are directed to the flagellin variant of claim 1, wherein the flagellin is derived from Vibrio vulnificus and the flagellin is flagellin B, respectively. As the deletions of claim 1 could be possible in these flagellin, the resultant variant would have a different sequence as the wildtype and would not be a product of nature.
Step 2A, Prong 2: If the claim is directed to a judicial exception, does the claim recite additional elements that integrate the judicial exception into a practical application? (MPEP 2106.05(a)-(c), (e)-(h))
Having determined that claims 1-4, 7-9, and 13-14 recite a judicial exception, it is then determined whether the claims recite additional element that integrate the judicial exception into a practical application.
Claims 1-4 do not include any additional elements to flagellin that lack the sequences to be deleted. The flagellin has no structural or functional changes from the wildtype, and it is not applied or used in any meaningful way beyond generally linking the use of the judicial exception to a particular technological environment. Regarding claims 7-9, since wildtype flagellin can have the effects claimed, these functional limitations do not include any additional elements to flagellin that lack the sequences to be deleted. The flagellin has no structural or functional changes from the wildtype, and it is not applied or used in any meaningful way beyond generally linking the use of the judicial exception to a particular technological environment.
Claims 13-14 only recite an intended use or field of use limitation of the wildtype flagellin since it does not affirmatively recite an action that effects a particular treatment or prophylaxis for a disease or medical condition. A vaccine composition containing an antigen, in itself, does not actually provide a treatment or prophylaxis.
MPEP 2106.04(d)(2) Particular Treatment and Prophylaxis in Step 2A Prong Two states:
“… [I]n order to qualify as a "treatment" or "prophylaxis" limitation for purposes of this consideration, the claim limitation in question must affirmatively recite an action that effects a particular treatment or prophylaxis for a disease or medical condition. An example of such a limitation is a step of "administering amazonic acid to a patient" or a step of "administering a course of plasmapheresis to a patient." If the limitation does not actually provide a treatment or prophylaxis, e.g., it is merely an intended use of the claimed invention or a field of use limitation, then it cannot integrate a judicial exception under the "treatment or prophylaxis" consideration. For example, a step of "prescribing a topical steroid to a patient with eczema" is not a positive limitation because it does not require that the steroid actually be used by or on the patient, and a recitation that a claimed product is a "pharmaceutical composition" or that a "feed dispenser is operable to dispense a mineral supplement" are not affirmative limitations because they are merely indicating how the claimed invention might be used.”
Therefore, claims 1-4, 7-9, and 13-14 do NOT recite additional elements that integrate the judicial exception into a practical application.
Step 2B: If the claim is directed to a judicial exception, determine whether any additional element, or combination of additional elements, in the claim is sufficient to ensure that the claim as a whole amounts to significantly more than the judicial exception. (MPEP 2106.05(d))
Having determined that claims 1-4, 7-9, do not integrate the judicial exception into a practical application, it is then determined whether any additional element in the claim is sufficient to ensure that claim as a whole amounts to significantly more than the judicial exception
Claims 1-4, 7-9 do not include any additional elements to flagellin that lack the sequences to be deleted. They each do not recite additional elements that ensure that each claim as a whole amounts to significantly more than the judicial exception.
As such, claims 1-4, 7-9, do not recite any additional element in the claim that is sufficient to ensure that claim as a whole amounts to significantly more than the judicial exception.
Claim Rejections - 35 USC § 102
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 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 1-4, 7-9, 13 are rejected under 35 U.S.C. 102102(a)(1) as being anticipated by Biedma et al (Biedma M., et al. Recombinant flagellins with deletions in domains D1, D2, and D3: Characterization as novel immunoadjuvants, Vaccine 37 (2019) 652–663, published 12/21/2018).
Regarding claim 1, Biedma et al teaches a flagellin variant in which N-terminal domain 2, domain 3, and C-terminal domain 2 is deleted in a flagellin or a fragment thereof (see Figure 1A, examples FliCΔ100-405, FliCΔ138-405, or FliCΔ161-405).
Claims 2-4, 7-9, and 13 depend on claim 1. The teachings of Biedma et al regarding claim 1 is incorporated in its entirety for claims 2-4, 7-9, and 13, and further described, as is relevant to each claim, below.
Regarding claim 2, Biedma et al further teaches the flagellin fragment originally included N-terminal domain 0, N-terminal domain 1, N-terminal domain 2, domain 3, C-terminal domain 2, C-terminal domain 1, and C- terminal domain 0 of wild-type flagellin. The flagellin variant was made from deleting sequences from the wildtype FliC flagellin from Salmonella enterica (see section 2.1 Production of recombinant flagellins).
Regarding claims 3-4, Biedma et al further teaches the flagellin variant is derived from a microorganism from the genus Salmonella, and specifically from the species Salmonella enterica (see section 2.1 Production of recombinant flagellins).
Regarding claims 7 and 9, Biedma et al further teaches some flagellin variants, including FliCΔ161-405, which has complete deletion of its domain 3 and domain 2 (Figure 1A), as is relevant to the flagellin variants in the claims, gave essentially equivalent in vivo TLR5-dependent innate immune responses following intranasal administration of 2 ug of flagellin to mice but decreased intrinsic antigenicity, compared to reference flagellin variant FliC Δ174-400 (Abstract and Figure 3). FliC Δ174-400 is used as a reference variant; it has deletion of domain 3 and partial deletion of domain 2, and has strongly impaired flagellin intrinsic antigenicity but no effect on its TLR5-dependent immunostimulatory activity (Abstract). As such, the FliCΔ161-405 variant, having equivalent functions, also has strongly impaired flagellin intrinsic antigenicity but no effect on its TLR5-dependent immunostimulatory activity. Specifically, the variant FliCΔ161-405 has comparable TLR5 stimulatory activity compared to the rFliC flagellin, which is the recombinant wildtype flagellin that served as the starting sequence that was mutated to create the variant FliCΔ161-405 (Figure 3). Finally, Biedma et al teaches that various researchers have reported that the deletion of domain 2 and domain 3 strongly abrogates flagellin’s intrinsic antigenicity but does not affect the protein’s immunostimulatory activity (page 654, first paragraph).
Therefore, the flagellin variants with deleted domain 3 and domain 2, retain toll-like receptor 5 (TLR5) stimulatory activity, as is relevant to claim 7, which is disclosed as a measure of the flagellin variants’ capacity to promote innate responses and adaptive response to co-administered antigens, as is relevant to claim 9 (Abstract).
Regarding claim 8, Biedma et al further teaches the flagellin variant induces no flagellin-specific immune response while the recombinantly expressed flagellin comprising the wildtype sequence induced a flagellin-specific antibody response. Biedma et al teaches that the flagellins’ intrinsic antigenicity was evaluated by two approaches (page 658, section 3.3 The activity of recombinant flagellins as mucosal adjuvants). The first approach is an analysis of the level of flagellin-specific antibody response elicited by in vivo vaccination of the flagellin or flagellin variant. From the results of this approach, Biedma et al teaches that only native flagellin FliC was able to elicit native flagellin FliC-specific antibodies, whereas the antigenicity of recombinant flagellins was abrogated, meaning production of FliC-specific antibody response was abrogated (page 658, section 3.3; and Figure 4C-D). The second approach is an in vitro measurement of the flagellin or flagellin variants’ cross-reactivity to highly potent FliC-specific “hyperimmune” serum. From the results of this approach, Biedma et al teaches that although an in vitro ELISA measurement shows that all flagellin variants are cross-reactive with a FliC-specific “hyperimmune” serum, they are all about ten-fold less cross-reactive than native FliC; and at the doses used for in vivo immunization, such antibodies responses are not elicited (page 658, section 3.3; and Figure 5). Therefore, the flagellin variants induced no, or not significant, flagellin-specific antibody responses in vivo. Finally, Biedma et al teaches that various researchers have reported that the deletion of domain 2 and domain 3 strongly abrogates flagellin’s intrinsic antigenicity but does not affect the protein’s immunostimulatory activity (page 654, first paragraph).
Regarding claim 13, Biedma et al further teaches a vaccine composition comprising of the flagellin variant and at least one antigen. Biedma et al administers the flagellin variants with ovalbumin (page 655, section 2.5 Animal Experiments), where ovalbumin is explicitly defined as a model antigen (page 658, section 3.3). The flagellin variants are developed as immunoadjuvants candidates for vaccination (Abstract).
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.
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.
Claims 5-6 are rejected under 35 U.S.C. 103 as being unpatentable over Biedma et al as applied to claims 1-4, 7-9, 13 above, and further in view of Lee et al (Lee, S., et al, A Bacterial Flagellin, Vibrio vulnificus FlaB, Has a Strong Mucosal Adjuvant Activity To Induce Protective Immunity, Infection And Immunity, Vol. 74, No. 1, published 01/2006) and further in view of Jia et al (Jia, P., et al, Comparative study of four flagellins of Vibrio anguillarum: Vaccine potential and adjuvanticity, Fish & Shellfish Immunology 34 (2013) 514e520, published 12/16/2012.)
Claims 5-6 depend on claim 1. The teachings of Biedma et al regarding claim 1 is incorporated in its entirety for claims 5-6, and further described, as is relevant to each claim, below.
Biedma et al further teaches that the sequences of the flagellin variants used in their experiments are based on flagellin FliC from Salmonella enterica, which is a well-described flagellin in the art that contains domain 2 and domain 3 (page 652, section Introduction, paragraph 1).
Biedma et al does not explicitly teach that the flagellin variant can be derived from Vibrio vulnificus, as in claim 5, or that the flagellin is flagellin B (FlaB), as in claim 6.
However, Lee et al teaches that a potent adjuvant would accelerate vaccine generation (page 701, paragraph5) and that flagellin FlaB derived from Vibrio vulnificus, which is an opportunistic pathogen, could be a more potent adjuvant than flagellin from Salmonella or other bacteria part of a normal flora (page 701, first paragraph). Lee et al further teaches wildtype FliC from Salmonella enterica showed less activation of Caco-2 cells, which is an indication of intrinsically lower TLR5-dependent immunstimulatory activity, than FlaB from Vibrio vulnificus (page 701, first paragraph). Accordingly, Lee et al further summarizes that different flagellins have different adjuvant activities based on their TLR5-dependent immunostimulatory activity (page 700, paragraph 2).
However, Lee et al does not specifically teach that FlaB has domains 2 and domains 3, as not all bacteria flagellin have all the domains.
Jia et al teaches that FlaB from the Vibrio genus consists of domain 2 and domain 3, and that these domains are linked to the production of flagellin-specific antibody (section Discussion, paragraph 1). Jia et al also corroborates that the conserved sequences in flagellin, specifically domain 1, hosts the recognition site for TLR5 (Introduction, paragraph 2).
It would be obvious to one skilled in the art, before the effective filing date of the instant application, to apply the technique of domain 2 and domain 3 deletion in flagellin taught by Biedma et al to the more immunostimulatory FlaB flagellin from the Vibrio vulnificus taught by Lee et al to arrive at the claimed invention. One skilled in the art would understand that since the domain 2 and domain 3 in FlaB triggers the same flagellin-specific antibody response as the domain 2 and domain 3 in FliC, as taught by Jia et al, one would have reasonable expectation of success that deleting these domains in FlaB would also yield a flagellin that induces a negligible flagellin-specific antibody response, but that still retains its TLR5-dependent immunostimulatory effects. One skilled in the art would be motivated to apply this technique taught by Biedma et al to the FlaB from Vibrio vulnificus taught by Lee et al because of its higher intrinsic TLR5-dependent immunostimulatory effects, leading to a potentially more potent adjuvant for vaccines.
KSR International Co. v. Teleflex Inc. (KSR), 550 U.S. 398, (2007), discloses that the use of known technique to improve similar products in the same way is obvious. In this case, the base product and known technique, as taught by Biedma et al, is the FliC flagellin and the deletion of the domain 2 and domain 3 regions to abrogate an flagellin-specific antibody response while maintaining its TLR5-dependent immunostimulatory effects. Jia et al teaches that FlaB flagellin is a comparable product to FliC, as it also comprises of domain 2 and domain 3 linked to inducing flagellin-specific antibody production. One of ordinary skill in the art would understand that the known technique could therefore be applied to FlaB, arriving at the claimed invention, as claimed in claims 5-6, and the results would have been predictable due to the shared structure-function correlation between the two flagellin.
Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over Biedma et al as applied to claims 1-4, 7-9, 13 above, and further in view of Holbrook et al (Holbrook, B., et al. Adjuvating an inactivated influenza vaccine with flagellin improves the function and quantity of the long-term antibody response in a nonhuman primate neonate model, Vaccine, Vol 34, Iss 39, published 09/07/2016).
Claim 14 depends on claim 1. The teachings of Biedma et al regarding claim 1 is incorporated in its entirety for claim 14, and further described, as is relevant to each claim, below. The teachings of Biedma et al regarding the use of the flagellin variant in a vaccine composition, as described regarding claim 13 above is also incorporated here.
Biedma et al does not explicitly teach flagellin variants as adjuvants specifically for flu vaccines.
However, Holbrook teaches a rationale to support the use of adjuvants, specifically flagellin, for influenza vaccination. Holbrook teaches there are no approved influenza vaccines for infants under six months old and that the main reason for this deficiency is the reported poor immunogenicity in very young infants (Introduction, paragraph 2), likely because the immune system of very young infants respond poorly, even following infection (Introduction, paragraph 3). Therefore, improving the immunogenicity of influenza vaccines is of vital importance to human health. Holbrook teaches their rationale for using flagellin for adjuvants in influenza vaccines come from previous mice studies demonstrating the inclusion of inactivated flagellin in an influenza vaccine resulted in increased protection (Introduction, paragraph 5). Holbrook et al further teaches that their studies demonstrate the ability of an influenza vaccine adjuvanted with flagellin to result in a significant increase in influenza virus-specific antibody production post vaccination and in long-term immune responses in neonates (Abstract), even though neonates normally have a relatively underdeveloped immune response compared to adults. Holbrook et al teaches a flu vaccine with a flagellin-based adjuvant that differed from the claimed invention only by the substitution of the specific flagellin-based adjuvant (Abstract).
It would be obvious to one skilled in the art, before the effective filing date of the instant application to substitute the flagellin variant adjuvant from Biedma et al into the flu vaccine containing another flagellin variant of Holbrook et al, arriving at the claimed invention. The specific flagellin based-adjuvant as taught by Biedma et al is an adjuvant for vaccines, in general. The effect of this flagellin based-adjuvant taught by Biedma et al comprises of maintaining TLR5-dependent immunostimulatory effects while abrogating flagellin-specific antibody production. Holbrook et al is silent on the flagellin-specific antibody production response to their flagellin-based adjuvant, but as they do not teach the domain 2 and domain 3 deletions, their flagellin variant could not be expected to have this advantage. One skilled in the art would be motivated to substitute the flagellin variant adjuvant from Biedma et al into the flu vaccine of Holbrook et al for the advantage of creating an adjuvant for a flu vaccine, for which there is a high need, and for the added advantage of the abrogated flagellin-specific antibody production response. This advantage is desirable since the generation of flagellin-specific antibodies can preclude the presence of adjuvant activity in future applications (Biedma et al, page 654, paragraph 4).
One skilled in the art would have reasonable expectation of success because Biedma et al has shown the flagellin variant acts as an adjuvant in vaccines due to its TLR5-dependent immunostimulatory effects and Holbrook et al notes that their flagellin works as potent adjuvant in their flu vaccine due in part to its ability to induce activation of dendritic cells, which is controlled by TLR5 agonism (page 4713, paragraph 3). Therefore, one skilled in the art would have reasonable expectation of success that the flagellin-based adjuvant taught for vaccines in general would be a successful adjuvant in flu vaccines because of its ability to activate the TLR5 immunostimulatory pathway.
KSR International Co. v. Teleflex Inc. (KSR), 550 U.S. 398, (2007), discloses that simple substitution of one known element for another to obtain predictable results is obvious. The substation of the flagellin variant taught by Biedma et al, which had disclosed advantages over the flagellin in the influenza vaccine taught by Holbrook et al, is an obvious and desirable substitution with a reasonable likelihood of success.
Double Patenting
Nonstatutory 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.
Application 18032902
Instant claims 1-5, 7-9, 13 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 of copending Application No. 18032902, claims filed 04/20/2023, hereafter referred to as Application 18032902, in view of Biedma et al. Although the claims at issue are not identical, they are not patentably distinct from each other. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding instant claim 1, copending Application 18032902 claim 1 is directed to a flagellin and a fragment or a variant thereof in a fusion protein. The instant application does not exclude the flagellin variant from being in a fusion protein. Claim 4 is directed to the flagellin comprising a conserved sequence recognized by toll-like receptor 5 (TLR5) and claim 5 is directed to the flagellin fragment having a hypervariable region removed from the wild-type flagellin. Biedma et al teaches the structure related to the function of these claims. Biedma et al teaches that earlier studies have shown that deletion of hypervariable domain 2 (D2) and domain 3 (D3) lead to the desired effect of negligible flagellin intrinsic antigenicity (page 654, paragraph 5). The flagellin’s TLR5-dependent immunostimulatory activity is linked to sequences on its conserved D0 and D1 domains (page 654, paragraph 4). In light of the structure-function correlation taught by Biedma et al, it would be obvious to one skilled in the art, before the effective filing date of the instant application, to understand that the flagellin variants with the claimed functions in Application 18032902 claims 1, 4, and 5 could be the flagellin with the domain deletions of instant claim 1.
Claims 2-5 and 7-13 depend on claim 1 and the teachings of Biedma et al above are incorporated herein.
Regarding instant claim 2, claim 6 and 7 of Application 18032902 further adds that the flagellin fragment comprises of the same flagellin domains or degree of sequence homology to the wildtype domains.
Regarding instant claims 3 and 4, claims 2 and 3 of Application 18032902 further discloses the same genera and species of microorganisms the flagellin can be derived from, respectively.
Regarding instant claim 5, claim 3 of Application 18032902 teaches the flagellin variant could be derived from Vibrio vulnificus.
Regarding instant claim 7, claim 4 of Application 18032902 is directed to the flagellin comprising a conserved sequence recognized by toll-like receptor 5 (TLR5), which one skill in the art would understand to mean the flagellin variant retains toll-like receptor 5 stimulatory activity.
Regarding instant claim 8, claim 5 of Application 18032902 is directed to the flagellin fragment having a hypervariable region removed from the wild-type flagellin, which one skilled in the art in view of the structure-function correlation taught by Biedma et al, as described above, would understand this would remove the flagellin-specific immune response.
Regarding instant claim 9, the immune boosting effect is defined by the instant specification as having both TLR5 immunostimulatory activity and negligible flagellin-specific immune response, which was discussed above, as relevant to instant claims 7 and 8.
Regarding instant claim 13, the flagellin variant as described above by claims 1, 4, and 5 is not explicitly taught in a vaccine by Application 18032902. Biedma et al further teaches that this flagellin variant is suitable as an adjuvant for a vaccine and teaches a vaccine composition comprising of this adjuvant. It would be obvious to one skilled in the art, before the effective filing date of the instant application, that the flagellin variant claimed in Application 18032902, having the same structure as the flagellin adjuvant in the instant claim, would also have reasonable likelihood of success as an adjuvant in a vaccine. Biedma et al teaches that major efforts have been made to develop flagellin into adjuvants for vaccines (page 654, paragraph 3), so one skilled in the art would also be motivated to combine this flagellin variant into a vaccine formulation as an adjuvant.
Instant claim 6 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 of copending Application No. 18032902, claims filed 04/20/2023, in view of Biedma et al as applied to instant claims 1-5, 7-9, 13 above, and further in view of Lee et al and further in view of Jia et al. Although the claims at issue are not identical, they are not patentably distinct from each other. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding instant claim 6, claims 1-5 teaches the flagellin variant with conserved sequences recognized by TLR5 and removed hypervariable region leading to negligible flagellin-specific immune response could be derived from Vibrio vulnificus. The teachings of Biedma et al in regards to the structure-function correlation of the flagellin variant is described above and incorporated herein.
Application 18032902 and Biedma et al does not explicitly state that the variant taught by claims 1-5 is derived from flagellin B (FlaB). However, Lee et al teaches that a potent adjuvant would accelerate vaccine generation (page 701, paragraph5) and that flagellin FlaB derived from Vibrio vulnificus, which is an opportunistic pathogen, could be a more potent adjuvant than flagellin from Salmonella or other bacteria part of a normal flora (page 701, first paragraph). Lee et al further teaches wildtype FliC from Salmonella enterica showed less activation of Caco-2 cells, which is an indication of intrinsically lower TLR5-dependent immunostimulatory activity, than FlaB from Vibrio vulnificus (page 701, first paragraph). Accordingly, Lee et al further summarizes that different flagellins have different adjuvant activities based on their TLR5-dependent immunostimulatory activity (page 700, paragraph 2).
However, Lee et al does not specifically teach that FlaB has domains 2 and domains 3, as not all bacteria flagellin have all the domains.
Jia et al teaches that FlaB from the Vibrio genus consists of domain 2 and domain 3, and that these domains are linked to the production of flagellin-specific antibody (section Discussion, paragraph 1). Jia et al also corroborates that the conserved sequences in flagellin, specifically domain 1, hosts the recognition site for TLR5 (Introduction, paragraph 2).
It would be obvious to one skilled in the art, before the effective filing date of the instant application, to apply the technique of domain 2 and domain 3 deletion in flagellin taught by Biedma et al to the more immunostimulatory FlaB flagellin from the Vibrio vulnificus taught by Lee et al to arrive at the claimed invention. One skilled in the art would understand that since the domain 2 and domain 3 in FlaB triggers the same flagellin-specific antibody response as the domain 2 and domain 3 in FliC, as taught by Jia et al, one would have reasonable expectation of success that deleting these domains in FlaB would also yield a flagellin that induces a negligible flagellin-specific antibody response, but that still retains its TLR5-dependent immunostimulatory effects. One skilled in the art would be motivated to apply this technique taught by Biedma et al to the FlaB from Vibrio vulnificus taught by Lee et al because of its higher intrinsic TLR5-dependent immunostimulatory effects, leading to a potentially more potent adjuvant for vaccines.
Claim 14 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 of copending Application No. 18032902, claims filed 04/20/2023, in view of Biedma et al and further in view of Holbrook et al. Although the claims at issue are not identical, they are not patentably distinct from each other. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding instant claim 14, Application 18032902 and Biedma et al does not explicitly teach that the flagellin variant taught by claims 1-5 can be used as an adjuvant specifically in a flu vaccine.
However, Holbrook teaches a rationale to support the use of adjuvants, specifically flagellin, for influenza vaccination. Holbrook teaches there are no approved influenza vaccines for infants under six months old and that the main reason for this deficiency is the reported poor immunogenicity in very young infants (Introduction, paragraph 2), likely because the immune system of very young infants respond poorly, even following infection (Introduction, paragraph 3). Therefore, improving the immunogenicity of influenza vaccines is of vital importance to human health. Holbrook teaches their rationale for using flagellin for adjuvants in influenza vaccines come from previous mice studies demonstrating the inclusion of inactivated flagellin in an influenza vaccine resulted in increased protection (Introduction, paragraph 5). Holbrook et al further teaches that their studies demonstrate the ability of an influenza vaccine adjuvanted with flagellin to result in a significant increase in influenza virus-specific antibody production post vaccination and in long-term immune responses in neonates (Abstract), even though neonates normally have a relatively underdeveloped immune response compared to adults. Holbrook et al teaches a flu vaccine with a flagellin-based adjuvant that differed from the claimed invention only by the substitution of the specific flagellin-based adjuvant (Abstract).
It would be obvious to one skilled in the art, before the effective filing date of the instant application, to substitute the flagellin variant adjuvant from Biedma et al into the flu vaccine containing another flagellin variant of Holbrook et al, arriving at the claimed invention. The specific flagellin based-adjuvant as taught by Biedma et al is an adjuvant for vaccines, in general. The effect of this flagellin based-adjuvant taught by Biedma et al comprises of maintaining TLR5-dependent immunostimulatory effects while abrogating flagellin-specific antibody production. Holbrook et al is silent on the flagellin-specific antibody production response to their flagellin-based adjuvant, but as they do not teach the domain 2 and domain 3 deletions, their flagellin variant could not be expected to have this advantage. One skilled in the art would be motivated to substitute the flagellin variant adjuvant from Biedma et al into the flu vaccine of Holbrook et al for the advantage of creating an adjuvant for a flu vaccine, for which there is a high need, and for the added advantage of the abrogated flagellin-specific antibody production response. This advantage is desirable since the generation of flagellin-specific antibodies can preclude the presence of adjuvant activity in future applications (Biedma et al, page 654, paragraph 4).
One skilled in the art would have reasonable expectation of success because Biedma et al has shown the flagellin variant acts as an adjuvant in vaccines due to its TLR5-dependent immunostimulatory effects and Holbrook et al notes that their flagellin works as potent adjuvant in their flu vaccine due in part to its ability to induce activation of dendritic cells, which is controlled by TLR5 agonism (page 4713, paragraph 3). Therefore, one skilled in the art would have reasonable expectation of success that the flagellin-based adjuvant taught for vaccines in general would be a successful adjuvant in flu vaccines because of its ability to activate the TLR5 immunostimulatory pathway.
Application 18032909
Instant claims 1-5, 7-9, 13 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 of copending Application No. 18032909, claims filed 04/20/2023, hereafter referred to as Application 18032909, in view of Biedma et al. Although the claims at issue are not identical, they are not patentably distinct from each other. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding instant claim 1, copending Application 18032909claim 1 is directed to a flagellin and a fragment or a variant thereof in a fusion protein. The instant application does not exclude the flagellin variant from being in a fusion protein. Claim 4 is directed to the flagellin comprising a conserved sequence recognized by toll-like receptor 5 (TLR5) and claim 5 is directed to the flagellin fragment having a hypervariable region removed from the wild-type flagellin. Biedma et al teaches the structure related to the function of these claims. Biedma et al teaches that earlier studies have shown that deletion of hypervariable domain 2 (D2) and domain 3 (D3) lead to the desired effect of negligible flagellin intrinsic antigenicity (page 654, paragraph 5). The flagellin’s TLR5-dependent immunostimulatory activity is linked to sequences on its conserved D0 and D1 domains (page 654, paragraph 4). In light of the structure-function correlation taught by Biedma et al, it would be obvious to one skilled in the art, before the effective filing date of the instant application, to understand that the flagellin variants with the claimed functions in Application 18032909 claims 1, 4, and 5 could be the flagellin with the domain deletions of instant claim 1.
Claims 2-5 and 7-13 depend on claim 1 and the teachings of Biedma et al above are incorporated herein.
Regarding instant claim 2, claim 6 and 7 of Application 18032909 further adds that the flagellin fragment comprises of the same flagellin domains or degree of sequence homology to the wildtype domains.
Regarding instant claims 3 and 4, claims 2 and 3 of Application 18032909 further discloses the same genera and species of microorganisms the flagellin can be derived from, respectively.
Regarding instant claim 5, claim 3 of Application 18032909 teaches the flagellin variant could be derived from Vibrio vulnificus.
Regarding instant claim 7, claim 4 of Application 18032909 is directed to the flagellin comprising a conserved sequence recognized by toll-like receptor 5 (TLR5), which one skill in the art would understand to mean the flagellin variant retains toll-like receptor 5 stimulatory activity.
Regarding instant claim 8, claim 5 of Application 18032909 is directed to the flagellin fragment having a hypervariable region removed from the wild-type flagellin, which one skilled in the art in view of the structure-function correlation taught by Biedma et al, as described above, would understand this would remove the flagellin-specific immune response.
Regarding instant claim 9, the immune boosting effect is defined by the instant specification as having both TLR5 immunostimulatory activity and negligible flagellin-specific immune response, which was discussed above, as relevant to instant claims 7 and 8.
Regarding instant claim 13, the flagellin variant as described above by claims 1, 4, and 5 is not explicitly taught in a vaccine by Application 18032909. Biedma et al further teaches that this flagellin variant is suitable as an adjuvant for a vaccine and teaches a vaccine composition comprising of this adjuvant. It would be obvious to one skilled in the art, before the effective filing date of the instant application, that the flagellin variant claimed in Application 18032909, having the same structure as the flagellin adjuvant in the instant claim, would also have reasonable likelihood of success as an adjuvant in a vaccine. Biedma et al teaches that major efforts have been made to develop flagellin into adjuvants for vaccines (page 654, paragraph 3), so one skilled in the art would also be motivated to combine this flagellin variant into a vaccine formulation as an adjuvant.
Instant claim 6 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 of copending Application No. 18032909, claims filed 04/20/2023, in view of Biedma et al as applied to instant claims 1-5, 7-9, 13 above, and further in view of Lee et al and further in view of Jia et al. Although the claims at issue are not identical, they are not patentably distinct from each other. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding instant claim 6, claims 1-5 teaches the flagellin variant with conserved sequences recognized by TLR5 and removed hypervariable region leading to negligible flagellin-specific immune response could be derived from Vibrio vulnificus. The teachings of Biedma et al in regards to the structure-function correlation of the flagellin variant is described above and incorporated herein.
Application 18032909 and Biedma et al does not explicitly state that the variant taught by claims 1-5 is derived from flagellin B (FlaB). However, Lee et al teaches that a potent adjuvant would accelerate vaccine generation (page 701, paragraph5) and that flagellin FlaB derived from Vibrio vulnificus, which is an opportunistic pathogen, could be a more potent adjuvant than flagellin from Salmonella or other bacteria part of a normal flora (page 701, first paragraph). Lee et al further teaches wildtype FliC from Salmonella enterica showed less activation of Caco-2 cells, which is an indication of intrinsically lower TLR5-dependent immunostimulatory activity, than FlaB from Vibrio vulnificus (page 701, first paragraph). Accordingly, Lee et al further summarizes that different flagellins have different adjuvant activities based on their TLR5-dependent immunostimulatory activity (page 700, paragraph 2).
However, Lee et al does not specifically teach that FlaB has domains 2 and domains 3, as not all bacteria flagellin have all the domains.
Jia et al teaches that FlaB from the Vibrio genus consists of domain 2 and domain 3, and that these domains are linked to the production of flagellin-specific antibody (section Discussion, paragraph 1). Jia et al also corroborates that the conserved sequences in flagellin, specifically domain 1, hosts the recognition site for TLR5 (Introduction, paragraph 2).
It would be obvious to one skilled in the art, before the effective filing date of the instant application, to apply the technique of domain 2 and domain 3 deletion in flagellin taught by Biedma et al to the more immunostimulating FlaB flagellin from the Vibrio vulnificus taught by Lee et al to arrive at the claimed invention. One skilled in the art would understand that since the domain 2 and domain 3 in FlaB triggers the same flagellin-specific antibody response as the domain 2 and domain 3 in FliC, as taught by Jia et al, one would have reasonable expectation of success that deleting these domains in FlaB would also yield a flagellin that induces a negligible flagellin-specific antibody response, but that still retains its TLR5-dependent immunostimulatory effects. One skilled in the art would be motivated to apply this technique taught by Biedma et al to the FlaB from Vibrio vulnificus taught by Lee et al because of its higher intrinsic TLR5-dependent immunostimulatory effects, leading to a potentially more potent adjuvant for vaccines.
Claim 14 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 of copending Application No. 18032909, claims filed 04/20/2023, in view of Biedma et al and further in view of Holbrook et al. Although the claims at issue are not identical, they are not patentably distinct from each other. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding instant claim 14, Application 18032909 and Biedma et al does not explicitly teach that the flagellin variant taught by claims 1-5 can be used as an adjuvant specifically in a flu vaccine.
However, Holbrook teaches a rationale to support the use of adjuvants, specifically flagellin, for influenza vaccination. Holbrook teaches there are no approved influenza vaccines for infants under six months old and that the main reason for this deficiency is the reported poor immunogenicity in very young infants (Introduction, paragraph 2), likely because the immune system of very young infants respond poorly, even following infection (Introduction, paragraph 3). Therefore, improving the immunogenicity of influenza vaccines is of vital importance to human health. Holbrook teaches their rationale for using flagellin for adjuvants in influenza vaccines come from previous mice studies demonstrating the inclusion of inactivated flagellin in an influenza vaccine resulted in increased protection (Introduction, paragraph 5). Holbrook et al further teaches that their studies demonstrate the ability of an influenza vaccine adjuvanted with flagellin to result in a significant increase in influenza virus-specific antibody production post vaccination and in long-term immune responses in neonates (Abstract), even though neonates normally have a relatively underdeveloped immune response compared to adults. Holbrook et al teaches a flu vaccine with a flagellin-based adjuvant that differed from the claimed invention only by the substitution of the specific flagellin-based adjuvant (Abstract).
It would be obvious to one skilled in the art, before the effective filing date of the instant application, to substitute the flagellin variant adjuvant from Biedma et al into the flu vaccine containing another flagellin variant of Holbrook et al, arriving at the claimed invention. The specific flagellin based-adjuvant as taught by Biedma et al is an adjuvant for vaccines, in general. The effect of this flagellin based-adjuvant taught by Biedma et al comprises of maintaining TLR5-dependent immunostimulatory effects while abrogating flagellin-specific antibody production. Holbrook et al is silent on the flagellin-specific antibody production response to their flagellin-based adjuvant, but as they do not teach the domain 2 and domain 3 deletions, their flagellin variant could not be expected to have this advantage. One skilled in the art would be motivated to substitute the flagellin variant adjuvant from Biedma et al into the flu vaccine of Holbrook et al for the advantage of creating an adjuvant for a flu vaccine, for which there is a high need, and for the added advantage of the abrogated flagellin-specific antibody production response. This advantage is desirable since the generation of flagellin-specific antibodies can preclude the presence of adjuvant activity in future applications (Biedma et al, page 654, paragraph 4).
One skilled in the art would have reasonable expectation of success because Biedma et al has shown the flagellin variant acts as an adjuvant in vaccines due to its TLR5-dependent immunostimulatory effects and Holbrook et al notes that their flagellin works as potent adjuvant in their flu vaccine due in part to its ability to induce activation of dendritic cells, which is controlled by TLR5 agonism (page 4713, paragraph 3). Therefore, one skilled in the art would have reasonable expectation of success that the flagellin-based adjuvant taught for vaccines in general would be a successful adjuvant in flu vaccines because of its ability to activate the TLR5 immunostimulatory pathway.
Conclusion
No claims are allowed.
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/B.C./Examiner, Art Unit 1645 January 15, 2026
/DANIEL E KOLKER/Supervisory Patent Examiner, Art Unit 1645