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 .
Election/Restrictions
Applicant’s election without traverse of Group I (methods of treating or preventing a disease or condition associated with a biofilm) and the species of an anti-DNABII antibody in the reply filed on 18 Aug 2026 is acknowledged. Claims 36-37 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention and claims 31 and 33 are withdrawn as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 18 Aug 2026.
Claim Status
The amended claim set filed 23 Jan 2025 is acknowledged. Claims 21-40 are currently pending. Of those, all claims are new. Claims 36-37 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention and claims 31 and 33 are withdrawn as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 18 Aug 2026. Claims 1-20 are cancelled. Claims 21-30, 32, 34-35, and 38-40 will be examined on the merits herein.
References to the specification in this action will use paragraph numbers found in the pre-grant publication (US-20250146046-A1; PTO-892).
Priority
The application claims priority to provisional application 63/046,314 (filed 30 June 2020) and is a CON of 17/364,578 (filed 30 June 2021). However, it appears that the provisional application fails to provide support for the method as claimed. Therefore, the effective filing date used for searching claims 23-30, 32, 34-35, and 38-40 is 30 Jun 2021. What follows is the examiner’s claim-by-claim analysis of effective filing date for the claims currently under examination. If the applicant disagrees with this examiner’s determination of effective filing date for any claim, the applicant may identify text within the prior applications that provides support the claimed language.
Regarding claims 21 and 38 (and their dependent claims), It is noted that the provisional discusses measuring antibiotic susceptibility of newly released (NRel) bacteria, such as at [0027-0028] and the data in Figure 3, but it appears that the provisional application only contemplated measuring antibiotic sensitivity at a single antibiotic concentration and comparing results across bacteria types, rather than comparing sensitivity of a single bacteria type at a “range of varying concentrations” as claimed. The only reference to a “range” is in [0056] of the provisional application in the context of defining the term “about.” Similarly, the only use of “vary” is in [0006] stating that antibiotic sensitivity varies, but not discussing a range of concentrations.
Also, the preamble of “treating or preventing a disease or condition associated with a biofilm in a subject in need thereof” is not supported by the provisional application. There are three uses of the term “prevent”, at pg. 4 (“Centers for Disease Control and Prevention”), and pg. 5 and 12, both in the context of using vaccines to prevent infection. Also, the step (b) of administering an antibody and antibiotic is not supported by the provisional application; the only use of the term “administer” is in the references (pg. 37).
Regarding claim 22 and 39, support cannot be found for the antibiotic sensitivity concentration being determined at 25% killing. There is no recitation of “25%”.
Regarding claims 24, support cannot be found for the bacterial species Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Enterobacter spp., or Aggregatibacter actinomycetemcomitans.
Regarding claim 26, support cannot be found for at least piperacillin and ceftazidime.
Regarding claim 27, support cannot be found for anti-IHF tip antibodies or anti-tip chimer antibodies (the only uses of “tip” are within other words such as “multiple”).
Regarding claim 28, support cannot be found for identifying the minimal inhibitory concentration. The only uses of “MIC” are within other words such as “proteomic” and the two uses of “minimal” are in unrelated contexts.
Regarding claim 29, the antibiotic sensitivity concentration being determined at 10-50% killing is not found in the provisional application. There is no recitation of “50%” and references to “50” are unrelated. Also, the only reference to “10%” (pg. 17) is unrelated.
Regarding claims 30 and 32, support cannot be identified for “pre-treat” or “about” in the context of the claimed durations. The only use of “about” is on pg. 32.
Regarding claim 34, as discussed above for claim 21, support was not identified for step (b).
Regarding claim 35, support cannot be identified for antibody CDRs.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 23 Jan 2025, 17 Oct 2025, and 18 Aug 2026 were filed in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements have been considered by the examiner. Signed copies of these statements are attached with this action.
For the IDS filed 23 Jan 2025, the copies of the foreign patent and non-patent literature documents were submitted in Application No. 17/364,578. Applicant is informed for future cases that 37 CFR 1.98(d) and MPEP 609.04(a) require that the prior application where copies were provided be identified in the IDS.
Claim Interpretation
The specification states at [0020]: “It is to be understood, although not always explicitly stated, that all numerical designations are preceded by the term "about".” In this action, this interpretation will be used when examining the claims. If the claims include numbers that should not be interpreted this way, the claims should be amended to clarify the applicant’s intent. For example, in claim 23, it seems plausible that the applicant’s intent may be for the antibiotic sensitivity to be determined using exactly two antibiotics, rather than about two antibiotics.
Regarding claims 23 and 40, the claims each recite “wherein the antibiotic sensitivity is determined for two antibiotics, optionally wherein the two antibiotics are selected from: glutamate and tobramycin, glutamate and colisin, trimethoprim and sulfamethoxazole, trimethoprim and clarithromycin, or amoxicillin and clavulanate.” MPEP 2143.03 states: “Language that suggests or makes a feature or step optional but does not require that feature or step does not limit the scope of a claim under the broadest reasonable claim interpretation.” Therefore, the optional antibiotic selection is interpreted as not limiting the claim.
Claim Objections
Claim 34 is objected to because of the following informalities: grammatical error; phrase duplicated. The claim recites “wherein step (b) comprises administering to the subject an anti-DNABII antibody or antigen-binding fragment thereof is administered to the subject.” It is believed that the second bolded reference to administration to the subject should be removed to improve grammar and resolve the redundancy. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 21-30, 32, 34-35 and 38-40 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 21, the preamble reads “a biofilm in a subject” and step (a) reads “a biofilm from the subject”. There is insufficient antecedent basis for the second recitation of “a biofilm” in the claim. The use of “a biofilm” with “the subject” (claiming antecedent basis back to the preamble) creates ambiguity about whether the biofilm in step (a) is the same or different biofilm compared to the one that is treated in the preamble.
Also, step (b)(i) reads “an anti-rsPilA antibody, an anti-DNABII antibody, or an antigen-binding fragment thereof”. There is insufficient antecedent basis for this limitation because part (a)(i) already recited these antibodies and one of ordinary skill in the art could not clearly determine whether the antibodies are the same or different compared the previously described ones.
Also, step (b)(ii) reads: “(b) administering to the subject… (ii) one or more antibiotics determined in step (a)(iii) as having antibiotic sensitivity to the NRel from the biofilm from the subject.” This references step (a)(iii): “determining the range of varying concentrations of one or more antibiotics that inhibit the growth of the NRel bacteria, thereby identifying antibiotic sensitivity;”. There is insufficient antecedent basis for the use of “one or more antibiotics determined in step (a)(iii)” in the claim. Step (a)(iii) does not determine antibiotics, instead it determines a “range of varying concentrations”. This unclear antecedent basis also means the claim does not clearly lay out whether step (b)(iii) refers to administering antibiotics in a method comprising a single administration step at any concentration/dose, or whether step (b)(iii) refers to administering the “the range of varying concentrations of one or more antibiotics” using multiple administrations to administer a range of concentrations as indicated by the antecedent basis.
The claim is also indefinite because step (b)(iii) states that the antibiotics are sensitive to NRel bacteria, but step (a)(iii) describes the opposite with bacteria being sensitive (inhibited growth) to the antibiotic.
In the interest of compact prosecution, in this action, the claim is interpreted as referring to two different biofilms (i.e. the identifying step can occur in vitro using a biofilm from the subject, but does not require a biofilm in the subject), referring to different antibodies from the same genus (i.e. the antibody used for treating does not need to have been used in the identifying step as long as it is within the claimed genus), and referring to administering any antibiotic where the NRel bacteria had antibiotic sensitivity (i.e. administration dose does not have to be related to the concentrations and ranges tested in the identifying step).
Claims 22-30, 32, and 34-35 are also rejected as indefinite because they depend from claim 21 and do not obviate these grounds of rejection.
Regarding claims 22 and 29, these claims each recite “The method of claim 21, wherein antibiotic sensitivity is determined when the concentration of the one or more antibiotics kills… of the bacteria”. There is insufficient antecedent basis for the limitation “antibiotic sensitivity is determined” because claim 21 step (a)(iii) recites that “the range of varying concentrations” is what is determined. Instead, antibiotic sensitivity is “identified”. In the interest of compact prosecution, in this action, the claim is interpreted as claiming that the concentration is determined to inhibit the growth of NRel bacteria when claimed the kill rate occurs. Although claim 21 step (a)(iii) is not indefinite itself, the examiner suggests that it might be amended so that other claims and phrases can reference the step more easily.
Regarding claim 26, the claim reads “the one or more antibiotics determined in step (a)(iii) as having antibiotic sensitivity to the NRel from the biofilm from the subject…” The antecedent basis is insufficient for this limitation because it is unclear whether this is limiting the antibiotics tested in step (a)(iii) or whether it is limiting the antibiotics administered to the subject in step (b)(ii).
Also, similar to the rejection of claim 21 above, this claim states that the antibiotics are sensitive to NRel bacteria, but step (a)(iii) describes the opposite with bacteria being sensitive (inhibited growth) to the antibiotic.
Also, similar to the rejection of claims 22 and 29 above, there is insufficient antecedent basis for the limitation “antibiotics determined” because claim 21 step (a)(iii) recites that “the range of varying concentrations” is what is determined. Instead, antibiotic sensitivity is “identified”.
Also, claim 26 recites “the one or more antibiotics … comprises one or more of piperacillin, ceftazidime,…[etc.]”. The claim is also indefinite because the specification does not define what is meant for an antibiotic to comprise piperacillin, ceftazidime, etc., which have defined chemical structures. One of ordinary skill in the art would not be able to determine whether the claim refers to chemicals with the antibiotics as sub-structures within them, or whether the choice of antibiotics is selected from a group comprising the listed antibiotics. If the second, then the claim is also indefinite because “If a Markush grouping requires a material selected from an open list of alternatives (e.g., selected from the group "comprising" or "consisting essentially of" the recited alternatives), the claim should generally be rejected under 35 U.S.C. 112(b) as indefinite because it is unclear what other alternatives are intended to be encompassed by the claim. See In re Kiely, 2022 USPQ2d 532 at 2* (Fed. Cir. 2022)” (MPEP 2173.05(h)).
In the interest of compact prosecution, in this action, the claim is interpreted as being met if one of the listed antibiotics is tested and shown to be effective for inhibiting growth of NRel bacteria, or if one of the listed antibiotics is administered. Although claim 21 step (a)(iii) is not indefinite itself, the examiner suggests that it might be amended so that other claims and phrases can reference the step more easily.
Regarding claims 26 and 30, where applicant acts as his or her own lexicographer to specifically define a term of a claim contrary to its ordinary meaning, the written description must clearly redefine the claim term and set forth the uncommon definition so as to put one reasonably skilled in the art on notice that the applicant intended to so redefine that claim term. Process Control Corp. v. HydReclaim Corp., 190 F.3d 1350, 1357, 52 USPQ2d 1029, 1033 (Fed. Cir. 1999). The term “glutamate” in claims 26 and 30 is used by the claim to mean “an antibiotic,” while the accepted meaning is “an amino acid.” (Brosnan et al. 2012; PTO-892). The term is indefinite because the specification does not clearly redefine the term. In the interest of compact prosecution, the term “antibiotic” will be interpreted using its customary meaning in the art. The examiner would consider evidence that glutamate can function as an antibiotic, if it were provided.
Regarding claims 27, 30 and 35, these claims recite “the anti-DNABII antibody or the antigen- binding fragment thereof”. There is insufficient antecedent basis for this limitation because claim 21 already recites “an anti-DNABII antibody, or an antigen-binding fragment thereof” in two different locations (part (a)(i) and (b)(i)) and one of ordinary skill would not be able to demine which definition from claim 21 is referred to in the dependent claims. In the interest of compact prosecution, in this action, the claim is interpreted the claim is interpreted as referring to either of the two antibodies of claim 21 (note the claim interpretation used for claim 21 did not require the antibody to be the same).
Regarding claim 32, the claim recites “an anti-DNABII antibody, or an antigen-binding fragment thereof”. There is insufficient antecedent basis for this limitation because claim 21 already recited these antibodies and one of ordinary skill in the art could not clearly determine whether the antibodies are the same or different compared the previously described ones. In the interest of compact prosecution, in this action, the claim is interpreted as referring to either of the two antibodies of claim 21 (note the claim interpretation used for claim 21 did not require the antibody to be the same).
Regarding claim 38, “administering” part (ii) reads “one or more antibiotics determined in step (a)(iii)”. There is insufficient antecedent basis for this term because there is no step (a)(iii) in this claim. Also, if this refers to the “wherein” clause step (iii), the recitation is indefinite because that step does not determine antibiotics, instead it determines a “range of varying concentrations”. This unclear antecedent basis also means the claim does not clearly lay out whether the administration step refers to administering antibiotics in a method comprising a single administration step at any concentration/dose, or whether the step refers to administering the “the range of varying concentrations of one or more antibiotics” using multiple administrations to administer a range of concentrations as indicated by the antecedent basis.
Also, claim scope cannot be clearly determined because one of ordinary skill in the art would not be able to determine whether infringement of the method requires that the steps in the “wherein” clause be performed, and would not be able to determine which antibiotics are claimed because the wherein clause determines the range of concentrations that the bacteria are susceptible to rather than determining a genus of antibiotics that could be used for treatment.
Also, the “wherein” clause refers to “a biofilm”. There is insufficient antecedent basis for this term because the claim 38 preamble also refers to “a biofilm” and claim scope cannot be unambiguously determined as it is not apparent whether or not the two biofilms are the same. Also, the “wherein” clause refers to “the biofilm”. There is insufficient antecedent basis for this term because the term “a biofilm” is defined twice and it is not apparent which one is being referred back to.
Also, the “wherein” clause refers to “an anti- rsPilA antibody, an anti-DNABII antibody, or an antigen-binding fragment thereof”. There is insufficient antecedent basis for this term because the administering step also refers to “an anti-rsPilA antibody, an anti-DNABII antibody, or an antigen-binding fragment thereof” and claim scope cannot be unambiguously determined as it is not apparent whether or not the two antibodies are the same.
In the interest of compact prosecution, in this action, the claim is interpreted with step(a)(iii) referring to step (iii) of the “wherein” clause similar to claim 21, with the “wherein” clause not required to be performed as part of the method and instead as if it refers to a process for identifying the genus of antibiotics should be administered. Additionally, the claim is interpreted as referring to administering any antibiotic where the NRel bacteria had antibiotic sensitivity (i.e. administration dose does not have to be related to the concentrations and ranges tested in the identifying step), the claim is interpreted as referring to two different biofilms (i.e. the wherein clause can occur in vitro and does not require a biofilm in the subject), and referring to different antibodies from the same genus (i.e. the antibody used for treating does not need to have been used in the identifying step as long as it is within the claimed genus).
Claims 39-40 are also rejected because they depend from claim 38 and do not obviate these grounds of rejection.
Regarding claims 39-40, each claim recites “antibiotic sensitivity is determined”. There is insufficient antecedent basis for the limitation “antibiotic sensitivity is determined” because the wherein clause recites that “the range of varying concentrations” is what is determined. Instead, antibiotic sensitivity is “identified”. In the interest of compact prosecution, in this action, the claim is interpreted as claiming that the concentration is determined to inhibit the growth of NRel bacteria when claimed the kill rate occurs. The examiner suggests that the “wherein” clause of claim 38 might be amended so that other claims and phrases can reference the step more easily.
Regarding claim 39, the claim has a grammatical error that renders the claim scope indefinite. The claim recites “antibiotic sensitivity is determined when the concentration of the one or more antibiotics that kills at least 25% of the NRel bacteria.” The claim does not answer the question, the antibiotic sensitivity is determined when the concentration does what? In the interest of compact prosecution, in this action, the claim is interpreted the same as claim 22 (without the word “that”, so that “kills” acts as a verb rather than modifying the concentration).
Claim Rejections - 35 USC § 112(a)
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 21-30, 32, 34-35 and 38-40 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.
Regarding claims 21-30, 32, and 34-35 only, these claims recite “identifying antibiotic sensitivity of a newly released bacteria (NRel bacteria) from a biofilm from the subject”. The biofilm being from the subject specifically, rather than being any generic biofilm, was not present in the application as filed. Instead, it was added in a new claim with the 23 Jan 2025 claim amendment. The arguments filed 23 Jan 2025 do not point out support for this limitation; instead they state “Support for the new claims can be found throughout the specification as filed. See, e.g., Specification as filed, paragraphs [0083], [0127]-[0135], [0155].” A review of those locations does not reveal teachings related to obtaining a biofilm from a subject for testing. Support also cannot be found elsewhere in the specification, including the examples, for obtaining a biofilm from a subject for testing; instead the examples describe establishing new biofilms using planktonic bacteria for testing [0162]. Also a search for “biofilm from the subject” reveals that this term is not used in the specification. Therefore, these claims are rejected as lacking adequate written description because the support for the limitation is not apparent, and applicant has not pointed out where the newly added limitation is supported.
Regarding claims 21-30, 32, 34-35 and 38-40, the scope of treatment methods administering antibodies and antibiotics is broader than what is described in the specification so that one of ordinary skill in the art would recognize possession of an invention. Instead, the specification only adequately describes treatment methods using dosages where the antibody or antibiotic would be effective for treatment alone as described in the art, and does not describe any additional antibodies or in vivo treatment or prevention methods using them that were not previously known to the art for treatment use.
MPEP 2163 states:
An original claim may lack written description support when (1) the claim defines the invention in functional language specifying a desired result but the disclosure fails to sufficiently identify how the function is performed or the result is achieved or (2) a broad genus claim is presented but the disclosure only describes a narrow species with no evidence that the genus is contemplated. See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1349-50 (Fed. Cir. 2010) (en banc). The written description requirement is not necessarily met when the claim language appears in ipsis verbis in the specification. "Even if a claim is supported by the specification, the language of the specification, to the extent possible, must describe the claimed invention so that one skilled in the art can recognize what is claimed. The appearance of mere indistinct words in a specification or a claim, even an original claim, does not necessarily satisfy that requirement." Enzo Biochem, Inc. v. Gen-Probe, Inc., 323 F.3d 956, 968, 63 USPQ2d 1609, 1616 (Fed. Cir. 2002).
Thus, the written description requirement may be satisfied through disclosure of function and minimal structure when there is a well-established correlation between structure and function. In contrast, without such a correlation, the capability to recognize or understand the structure from the mere recitation of function and minimal structure is highly unlikely. In this latter case, disclosure of function alone is little more than a wish for possession; it does not satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (written description requirement not satisfied by merely providing "a result that one might achieve if one made that invention"); In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming a rejection for lack of written description because the specification does "little more than outline goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate").
First, the claims state the broad limitation that any dose of antibiotic and antibody can be used. However, the antibody and antibiotic not capable of the use “treating or preventing a disease or condition associated with a biofilm in a subject” so broadly; the dose is critical for the claimed functional outcome of “treating or preventing a disease or condition associated with a biofilm”. The instant specification and art teach that antibiotics alone are insufficient to treat biofilm infections alone: “OM is still commonly treated with broad-spectrum oral antibiotics, which do not reach sufficient levels in the middle ear (or other sites) to eradicate biofilms or even the planktonically growing bacteria within this anatomical niche…” [0005]. The instant specification also demonstrates that there is a dose-dependent effect of “a humanized monoclonal antibody raised against a chimeric peptide identified as IhfA5-mIhfB4 tip chimer” for causing release of six different bacterial species from biofilms in vitro [Figure 8, 0013]. Therefore, the specification clearly indicates that the dose of both antibiotic and antibody at the site of infection are related to the functional “treating or preventing” effect.
However, the specification does not indicate what doses (alone or in combination) are capable of achieving the claimed effect in vivo. The instant specification does not provide any in vivo examples that could be used for understanding the dosage to administer.
The specification teaches “For any compound used in the methods, the therapeutically effective dose can be estimated initially from cell culture assays. A dose can be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 (i.e., the concentration of the test compound which achieves a half-maximal inhibition of symptoms) as determined in cell culture. Such information can be used to more accurately determine useful doses in humans.” [0072]. However, the specification does not describe how to “initially estimate” a therapeutically effective dose from cell culture assays such as those in the examples. The specification teaches “Factors affecting dose include physical and clinical state of the subject, route of administration, intended goal of treatment (alleviation of symptoms versus cure), and potency, stability, and toxicity of the particular composition.” [0066], and describes generally the routes of administration that might be used [0143-0146], but does not describe how to use these factors to choose the dosage administered.
The specification teaches that for “the interfering agent”, “Typically, the therapeutically effective daily dose will be at least about 1 mg, or at least about 10 mg, or at least about 100 mg, or about 200 to about 500 mg, and sometimes, depending on the compound, up to as much as about 1 g to about 2.5 g.” [0147], but does not provide a rationale for why these doses are believed to be therapeutically effective, does not teach that the “therapeutic effect” contemplated is doses of anti-DNABII antibodies that are administered with an antibiotic as in the claims in a “method of treating or preventing a disease or condition associated with a biofilm”. This general statement of a broad range of dosages that could potentially be administered would not be considered by one of ordinary skill in the art to demonstrate possession of the dosages of antibodies and antibiotics that should be used in the claimed treatment method.
Second, the interpretation being used in this action is that the antibody used for treating does not need to be the same antibody that was used for identifying antibiotic sensitivity, they just must both be from the same genus of “an anti-rsPilA antibody, an anti-DNABII antibody, or an antigen-binding fragment thereof” (elected species is an anti-DNABII antibody) (see this interpretation at par. 27, 42). This genus of antibodies is broad, and includes monoclonal and polyclonal antibodies from any species (human, mouse, rabbit, chicken, etc.) that bind to any part of the DNABII protein with any binding domain.
However, the specification provides evidence that the synergy observed is specific to the antibody-antibiotic pair. Figure 3A-E shows that the anti-IHF (an anti-DNABII antibody) only shows synergy with amoxicillin/clavulanate (AMC) and not with trimethoprim/sulfamethoxazole (TMP-SMX). The specification concludes “Taken together, this data suggested that the NRel phenotype is not ‘generic,’ but rather highly distinct and dependent on the antibody-mediated mechanism of release of NTHI from biofilm residence.” [0217] and that “ There were differences in terms of which of the three top-line antibiotics would likely be best for the patient in terms of relative benefit” [0016].
The specification does not provide any in vivo examples demonstrating treatment or prevention in a subject, as claimed. For in vitro examples, the specification tests the following antibodies:
“rabbit polyclonal IgG derived from anti-native IHF antiserum (generated against IHF isolated from NTHI strain 86-028NP)” [0163, 0184] tested with amoxicillin/clavulanate and trimethoprim/sulfamethoxazole [0164, 0190] in both Examples 1-2
“a humanized monoclonal antibody raised against a chimeric peptide identified as IhfA5-mIhfB4 tip chimer” with no antibiotic [0013, Figure 8]; and with “each of the three current top-line antibiotics used to treat individuals with disease due to the indicated pathogen” [0016, Figure 11].
“a murine anti-tip chimer antibody” that is both anti-DNABII and anti-rsPilA, tested with amoxicillin/clavulanate and trimethoprim/sulfamethoxazole [0014-0015, Figures 9-10]
“anti-DNABII”, no additional details, with tobramycin [0017, Figure 12]
In the parts of the specification other than the examples, the specification also describes an anti-DNABII antibody with the CDRs of claim 35 in [0084] but does not give any information about how it can be used to treat or prevent biofilms and which antibiotics it should be combined with. The specification does not describe which specific anti-DNABII antibodies should be used in an in vivo treatment method or describe which antibiotics they should be paired with.
It is well known in the that there are differences between in vitro and in vivo use of antibodies.
Kauvar et al. (US-20150197558-A1; PTO-892) describes specific properties that therapeutic antibodies must have: “For use in treatment of bacterial infection in humans, the binding moieties of the invention should have at least three characteristics in order to be maximally successful: the binding moiety should be compatible with the treated species—e.g., in the case of monoclonal antibodies for treating humans, either human or humanized. The binding moiety must have an affinity for the biofilm-forming DNABII protein that exceeds the affinity of that protein for other components of the biofilm that includes this DNABII protein, and it must be crossreactive across the DNABII homologs from multiple bacterial species, minimally two or three such species including both Gram positive and Gram negative species, but preferably a greater number, such as four, five or six or more.” [0024].
Ryser et al. (2019, “Human antibody repertoire…”; PTO-892) states: “We have cloned 21 such antibodies [anti-DNABII antibodies]. Aside from TRL1068 [a previously described antibody], only one (TRL1330) has all the biochemical properties believed necessary for pharmacological efficacy (broad spectrum epitope specificity and high affinity).” (Abstract).
Bakaletz et al. (WO-2018129092-A1; PTO-892) specifically discusses in vitro use when stating “In the case of an in vitro application, in some embodiments the effective amount will depend on the size and nature of the application in question. It will also depend on the nature and sensitivity of the in vitro target and the methods in use. The skilled artisan will be able to determine the effective amount based on these and other considerations.” [0094].
MPEP 2163 states: “disclosure of an antigen fully characterized by its structure, formula, chemical name, physical properties, or deposit in a public depository does not, without more, provide an adequate written description of an antibody claimed by its binding affinity to that antigen, even when preparation of such an antibody is routine and conventional. See Amgen Inc. v. Sanofi, 872 F.3d 1367, 1378, 124 USPQ2d 1354, 1361 (Fed. Cir. 2017)("knowledge of the chemical structure of an antigen [does not give] the required kind of structure-identifying information about the corresponding antibodies"); see also Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341, 1351-52, 97 USPQ2d 1870, 1877 (Fed. Cir. 2011) (patent disclosed the antigen the claimed antibody was supposed to bind, but did not disclose any antibodies with the specific claimed properties).” In contrast, MPEP 2163 also states: “Rasmussen, 650 F.2d at 1215, 211 USPQ at 327 ("one skilled in the art who read Rasmussen’s specification would understand that it is unimportant how the layers are adhered, so long as they are adhered") (emphasis in original), … Information which is well known in the art need not be described in detail in the specification. See, e.g., Hybritech, Inc. v. Monoclonal Antibodies, Inc., 802 F.2d 1367, 1379-80, 231 USPQ 81, 90 (Fed. Cir. 1986)”.
In this case, the art and specification teach that detailed information about the antibodies are required and the antigen’s disclosure is insufficient when it only describes the antigen (like in Amgen) because it is important which anti-DNABII antibody is chosen (unlike in Rasmussen) and it was not well known in the art which antibodies should be used for an in vivo application (unlike Hybritech). Similarly, the art and specification teach that detailed information about the antibody-antibiotic pair is important and that it was not well known which pairs of antibodies and antibiotics should be used together.
One of ordinary skill in the art would not have thought that the specification demonstrates possession of the claimed invention by disclosing the structure correlated with the claimed function because there is no in vivo example showing any pair of antibody and antibiotic has the claimed function. The treatment function is not correlated with the genus claimed, where any anti-DNABII antibody can be paired with any antibiotic, because the function is specific to the pairing and only a subset of antibodies have properties that make them suitable for use in an in vivo method.
The instant specification also does not demonstrate possession by measuring a representative sample of antibody-antibiotic pairs that have the functional limitation because there is no in vivo example showing any pair of antibody and antibiotic has the claimed function. Even for the in vitro data, the “rabbit polyclonal IgG derived from anti-native IHF antiserum” is known in the art to be incompatible with non-rabbit species of subject and there is no evidence provided that the serum has the sort of specificity, breadth, and affinity needed for in vivo use. The “a murine anti-tip chimer antibody” that binds both PilA and DNABII and “anti-DNABII” antibodies are only described generally with minimal information about even the antigen that is recognized by the antibody, and there also is no evidence provided that the serum has the sort of specificity, breadth, and affinity needed for in vivo use. Finally, the “a humanized monoclonal antibody raised against a chimeric peptide identified as IhfA5-mIhfB4 tip chimer” is not identified beyond this description and lacks the sort of detailed description required to demonstrate possession of the antibody, and also does not have evidence that the antibody has the affinity required for in vivo use. Also, one of ordinary skill in the art would not consider a single monoclonal antibody to be representative of the full genus of all possible antibodies that bind to the antigen DNABII.
Therefore, one of ordinary skill in the art would not have believed that the specification demonstrates possession of a treatment method that treats the genus of “an anti-rsPilA antibody, an anti-DNABII antibody, or an antigen-binding fragment thereof” as interchangeable and that uses any possible antibody-antibiotic pair. Instead, the specification only adequately describes treatment methods using dosages where the antibody or antibiotic would be effective for treatment alone as described in the art, and does not describe any additional antibodies or in vivo treatment or prevention methods using them that were not previously known to the art for treatment use.
Claims 21-30, 32, 34-35 and 38-40 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for (1) identifying antibiotic sensitivity using experimentally created biofilms and (2) using specific anti-DNABII antibodies known in the art at doses known in the art to treat biofilm infections, does not reasonably provide enablement for (1) using biofilms from the subject and (2) use of any anti-DNABII antibody in an in vivo method of treating or preventing a disease or condition associated with a biofilm in a subject. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The factors to be considered in determining whether a disclosure would require undue experimentation include: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. In re Wands, 8 USPQ2d, 1400 (CAFC 1988) and MPEP 2164.01. Although all factors were considered, the Wands factors that were most relevant for this decision are discussed in detail below.
The breadth of the claims: Regarding claims 21-30, 32, and 34-35 only, these claims recite “identifying antibiotic sensitivity of a newly released bacteria (NRel bacteria) from a biofilm from the subject”. This subject in need of “treating or preventing a disease or condition associated with a biofilm in a subject”.
Regarding claims 21-30, 32, 34-35 and 38-40, the claims state that any dose of antibiotic and antibody can be administered to obtain the effect of “treating or preventing a disease or condition associated with a biofilm in a subject”, and the interpretation being used in this action is that the antibody used for treating does not need to be the same antibody that was used for identifying antibiotic sensitivity, they just must both be from the same genus of “an anti-rsPilA antibody, an anti-DNABII antibody, or an antigen-binding fragment thereof” (elected species is an anti-DNABII antibody). This genus of antibodies is broad, and includes monoclonal and polyclonal antibodies from any species (human, mouse, rabbit, chicken, etc.) that bind to any part of the DNABII protein with any binding domain.
The amount of direction provided by the inventor and the existence of working examples: The specification has no disclosure or working examples of how to obtain a biofilm from the subject. Instead the examples describe establishing new biofilms using planktonic bacteria for testing [0162]. The specification also does not describe how to obtain a biofilm from a subject who has not yet had the disease or condition associated with the biofilm (note that the claim requires prevention in addition to treatment).
Relating to dosing, the instant specification and art teach that antibiotics alone are insufficient to treat biofilm infections alone: “OM is still commonly treated with broad-spectrum oral antibiotics, which do not reach sufficient levels in the middle ear (or other sites) to eradicate biofilms or even the planktonically growing bacteria within this anatomical niche…” [0005]. The instant specification also demonstrates that there is a dose-dependent effect of “a humanized monoclonal antibody raised against a chimeric peptide identified as IhfA5-mIhfB4 tip chimer” for causing release of six different bacterial species from biofilms in vitro [Figure 8, 0013]. Therefore, the specification clearly indicates that the dose of both antibiotic and antibody at the site of infection are related to the functional “treating or preventing” effect.
However, the specification does not indicate what doses (alone or in combination) are capable of achieving the claimed effect in vivo. The instant specification does not provide any in vivo examples that could be used for understanding the dosage to administer.
The specification teaches “For any compound used in the methods, the therapeutically effective dose can be estimated initially from cell culture assays. A dose can be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 (i.e., the concentration of the test compound which achieves a half-maximal inhibition of symptoms) as determined in cell culture. Such information can be used to more accurately determine useful doses in humans.” [0072]. However, the specification does not teach how to “initially estimate” a therapeutically effective dose from cell culture assays such as those in the examples. The specification teaches “Factors affecting dose include physical and clinical state of the subject, route of administration, intended goal of treatment (alleviation of symptoms versus cure), and potency, stability, and toxicity of the particular composition.” [0066], and describes generally the routes of administration that might be used [0143-0146], but does not describe how to use these factors to choose the dosage administered.
The specification teaches that for “the interfering agent”, “Typically, the therapeutically effective daily dose will be at least about 1 mg, or at least about 10 mg, or at least about 100 mg, or about 200 to about 500 mg, and sometimes, depending on the compound, up to as much as about 1 g to about 2.5 g.” [0147], but does not provide a rationale for why these doses are believed to be therapeutically effective, does not teach that the “therapeutic effect” contemplated is doses of anti-DNABII antibodies that are administered with an antibiotic as in the claims in a “method of treating or preventing a disease or condition associated with a biofilm”.
Relating to the antibody-antibiotic pair chosen, the specification provides evidence that the synergy observed is specific to the antibody-antibiotic pair. Figure 3A-E shows that the anti-IHF (an anti-DNABII antibody) only shows synergy with amoxicillin/clavulanate (AMC) and not with trimethoprim/sulfamethoxazole (TMP-SMX). The specification concludes “Taken together, this data suggested that the NRel phenotype is not ‘generic,’ but rather highly distinct and dependent on the antibody-mediated mechanism of release of NTHI from biofilm residence.” [0217] and that “ There were differences in terms of which of the three top-line antibiotics would likely be best for the patient in terms of relative benefit” [0016].
The specification does not provide any in vivo examples demonstrating treatment or prevention in a subject, as claimed. For in vitro examples, the specification tests the following antibodies:
“rabbit polyclonal IgG derived from anti-native IHF antiserum (generated against IHF isolated from NTHI strain 86-028NP)” [0163, 0184] tested with amoxicillin/clavulanate and trimethoprim/sulfamethoxazole [0164, 0190] in both Examples 1-2
“a humanized monoclonal antibody raised against a chimeric peptide identified as IhfA5-mIhfB4 tip chimer” with no antibiotic [0013, Figure 8]; and with “each of the three current top-line antibiotics used to treat individuals with disease due to the indicated pathogen” [0016, Figure 11].
“a murine anti-tip chimer antibody” that is both anti-DNABII and anti-rsPilA, tested with amoxicillin/clavulanate and trimethoprim/sulfamethoxazole [0014-0015, Figures 9-10]
“anti-DNABII”, no additional details, with tobramycin [0017, Figure 12]
In the parts of the specification other than the examples, the specification also describes an anti-DNABII antibody with the CDRs of claim 35 in [0084] but does not give any information about how it can be used to treat or prevent biofilms and which antibiotics it should be combined with. The specification does not describe which specific anti-DNABII antibodies should be used in an in vivo treatment method or describe which antibiotics they should be paired with.
The state of the prior art and the level of predictability in the art: The art at the time of filing also used new biofilms established from planktonic bacteria, like in the specification’s examples, rather than biofilms from the subject, like in the claims. For example, see Kauvar et al. (US-20150197558-A1; PTO-892) [0097] which forms biofilms in a microplate rather than obtaining them from a subject.
It is well known in the that there are differences between in vitro and in vivo use of antibodies.
Kauvar et al. (US-20150197558-A1; PTO-892) describes specific properties that therapeutic antibodies must have: “For use in treatment of bacterial infection in humans, the binding moieties of the invention should have at least three characteristics in order to be maximally successful: the binding moiety should be compatible with the treated species—e.g., in the case of monoclonal antibodies for treating humans, either human or humanized. The binding moiety must have an affinity for the biofilm-forming DNABII protein that exceeds the affinity of that protein for other components of the biofilm that includes this DNABII protein, and it must be crossreactive across the DNABII homologs from multiple bacterial species, minimally two or three such species including both Gram positive and Gram negative species, but preferably a greater number, such as four, five or six or more.” [0024].
Ryser et al. (2019, “Human antibody repertoire…”; PTO-892) states: “We have cloned 21 such antibodies [anti-DNABII antibodies]. Aside from TRL1068, only one (TRL1330) has all the biochemical properties believed necessary for pharmacological efficacy (broad spectrum epitope specificity and high affinity).” (Abstract).
Bakaletz et al. (WO-2018129092-A1; PTO-892) specifically discusses in vitro use when stating “In the case of an in vitro application, in some embodiments the effective amount will depend on the size and nature of the application in question. It will also depend on the nature and sensitivity of the in vitro target and the methods in use. The skilled artisan will be able to determine the effective amount based on these and other considerations.” [0094].
The quantity of experimentation needed to make or use the invention: The standard of an enabling disclosure is not the ability to make and test if the invention works but one of the ability to make and use with a reasonable expectation of success and without undue experimentation. A patent is granted for a completed invention, not the general suggestion of an idea (MPEP 2164.03 and Chiron Corp. v. Genentech Inc., 363 F.3d 1247, 1254, 70 USPQ2d 1321, 1325-26 (Fed. Cir. 2004). The instant specification is not enabling because one cannot follow the guidance presented therein, or within the art at the time of filing, and practice the claimed method without first making a substantial inventive contribution.
Given that obtaining a biofilm from a subject is not described in the specification and is also not routine in the art, there would be a substantial amount of experimentation to identify how to successfully obtain a biofilm from the subject, especially those subjects in need of prevention of a disease or condition associated with the biofilm, with no guidance from the specification.
Given that the nature of the invention is in vivo prevention and treatment of a range of diseases and conditions associated with biofilms, a person having ordinary skill in the art would have to perform multiple further in vivo experiments in human clinical trials or in animal models that are predictive of treatment in a representative number of diseases and conditions associated with biofilms, that test a representative number of antibiotic-antibody pairs at a representative number of dosages, in order to demonstrate that the invention could be used with a reasonable expectation of success. Notably, Ryser shows that there is a very low expectation of success when searching for antibodies that are suitable for pharmacological use (1/21 tested), and the instant specification shows that the antibody-antibiotic pairing is specific but does not provide any way to predict which pairings will be successful, so each pairing must be tested individually.
The amount of experimentation required for enabling guidance, commensurate in scope with what is claimed, goes beyond what is considered ‘routine' within the art, and constitutes undue further experimentation in order to use the method with a reasonable expectation of successfully preventing and treating a range of diseases and conditions associated with biofilms. However, the art enables the in vivo therapies that were already well known at the time of filing. Therefore, claims 21-30, 32, 34-35 and 38-40 are rejected under 35 U.S.C. §112(a) or 35 U.S.C. §112, first paragraph, for failing to meet the enablement requirement, commensurate in scope with what is claimed.
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.
Claims 38-40 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Novotny et al. (2016, “Monoclonal antibodies…”; first made of record in IDS filed 23 Jan 2025, copy included with PTO-892).
Regarding claim 38 “administering”, Novotny teaches study where mice were administered MAbs IhfA5NTHI + mIhfB4NTHI + tobramycin (Table 1). The administration was used in a mouse P. aeruginosa lung infection model (section 3.5 header, Figure 5). Novotny teaches “treatment with antibodies directed against a DNABII protein (or derived peptide) induced collapse of the biofilm with release of viable resident bacteria,” (pg. 41 col. 2 par. 2), so the subject (mouse) has “a disease or condition associated with a biofilm in a subject” (biofilm infection).
Regarding claim 38 “wherein” and claims 39-40, Novotny does not teach the wherein clause’s description of identifying antibiotic sensitivity of NRel, or the additional limitations on the wherein clause from dependent claims 39-40. As stated above (par. 42), “In the interest of compact prosecution, in this action, the claim is interpreted with step(a)(iii) referring to step (iii) of the “wherein” clause similar to claim 21, with the “wherein” clause not required to be performed as part of the method and instead as if it refers to a process for identifying the genus of antibiotics should be administered.” Instant claim 40 teaches that tobramycin is an example of an antibiotic that can be used to identify antibiotic susceptibility with the identifying method, so it is within the genus of antibodies that can be administered in the method of claims 38-40.
Pertinent Prior Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. The following art is relevant to the “identifying” step and was cited in the parent application 17/364,578 (now Patent No. 12,116,614; PTO-892). Goodman et al. (US-20110236306-A1; hereafter Goodman; IDS filed 23 Jan 2025) teaches a method of generating newly released (NRel) bacteria by treating a biofilm with anti-IHF serum and collecting bacteria in the supernatant at 1, 2, and 4 hour timepoints [Figure 4B]. Goodman also teaches that there is a synergistic effect on biofilm disruption when the anti-IHF antibody is used in combination with the antibiotic amoxicillin [0539; Figure 14C IV]. However, Goodman does not teach a step of contacting the NRel bacteria released by anti-IHF pre-treatment with a range of varying concentrations of antibiotics to determine the antibiotic sensitivity. Similarly, Mokrzan et al. (2018; IDS filed 23 Jan 2025, additional copy included with PTO-892) teaches disrupting biofilms with anti-rsPilA antibodies for durations of 6 or 7 h for biofilms formed at 37°C or 34°C, respectively (pg. 16 par. 1) and teaches that these durations were chosen to “achieve maximal dispersion” (Figure 5 legend on pg. 8). Mokrzan does not teach determining antibiotic sensitivity “with a range of varying concentrations” of the candidate agent(s), as required by claims 1 and 3. Testing NRel susceptibility to multiple different concentrations of antibiotics requires isolating them. Therefore, one of ordinary skill would be motivated to choose a longer, non-claimed treatment duration when using antibodies to disrupt the biofilm in order to follow the teachings of the field and obtain greater numbers of released bacteria to test. Choosing a shorter time period of about 15 minutes to about 4 hours, where it is known that fewer bacteria are released, would not have been obvious.
Conclusion
No claims are allowed.
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AMELIA N DICKENS
Examiner
Art Unit 1645
/AMELIA NICOLE DICKENS/Examiner, Art Unit 1645
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