DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of Claims
Claims 1, 6-9, 16-17, 19-21, 24-25, 28-31, 33, 35, and 39-40 are pending in the application and are being examined on the merits.
Priority
The present application claims status as a 371 (National Stage) of PCT/US22/73367 filed on 07/01/2022. Applicant’s claim for benefit under 35 U.S.C. 119(e) of Provisional application 63/217,384 filed on 07/01/2021 is acknowledged. The present application and all claims are being examined with the earliest effective filing date of 07/01/2021.
Information Disclosure Statement
The information disclosure statements (IDS) filed 12/29/2023 and 04/15/2024 have been considered by the examiner.
Drawings
The drawings are objected to because:
Fig. 2A: The shading of the different elements are too similar to differentiate them. In addition, many of the data points are too small and/or blurry to distinguish their designated shape (i.e., circle versus triangle).
Fig. 2B: The shading is too similar amongst the different genera to identify and distinguish them from one another in the figure.
FIG. 3: The brief description states "the colors correspond to specific microbiome biotypes" (pg. 2, para. [0008]). However, there is no legend or further description that identifies what "specific biotypes" correspond to the different shades of gray.
FIG. 4A-4D: The brief description states "Bacterial genera that increase in relative abundance with the exposure are shown as yellow bars" and those "that decrease in relative abundance with the exposure are shown as blue bars" (pg. 3, para. [0009]). However, the figures are in grayscale, and there is no legend to identify which bars belong to each group.
FIG. 5A-5F: There are multiple growth curves in each figure with slightly different shading, but none of them are identified, either by a legend or in the brief description. Note that even if these curves were identified by a legend or further description, they would still be difficult to distinguish due to similar shading and appearance.
FIG. 9A-9B: The shading and appearance of the lines/symbols of the different growth media are too similar to distinguish them from one another.
FIG. 13: The shading of the lines in the figure are too similar to one another to identify which line is associated with each effect size.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
Claim 8 is objected to because of the following informalities: the claim recites “comprises least 103” in line 2 which appears to be a typographical error. Please amend the claim to recite “comprises at least 103” in line 2. Appropriate correction is required.
Claim 25 is objected to because of the following informalities: please amend “S. pneumoniae, H. influenzae” to recite “Streptococcus pneumoniae, Haemophilus influenzae”. It is proper to present claim elements (e.g., genera) in their unabbreviated form the first time they are introduced in the claims. Appropriate correction is required.
Claim Interpretation
Claim 16 recites a method of promoting respiratory health in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a formulation, wherein the growth and/or colonization of pathogenic bacteria in the subject’s respiratory system is inhibited and/or prevented. “Promoting respiratory health” in a subject and “preventing the colonization” of pathogenic bacteria in the subject’s respiratory system does not require the subject to have any particular health status (e.g., infection, asthma, etc.). Hence, under the broadest reasonable interpretation of the claim, the “subject” of claim 16 is directed to any subject having a respiratory system.
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 and 6-9 are rejected under 35 U.S.C. 101 because the claimed invention is directed to the judicial exception of a natural product without significantly more. The rationale for this determination is explained below and is in keeping with the latest guidance regarding analysis of judicially excepted subject matter.
Subject Matter Eligibility Guidance
A three-step inquiry has been established to determine subject matter eligibility under 35 U.S.C. 101, in accordance with MPEP § 2106:
Step 1 – Is the claim directed to a process, machine, manufacture, or composition of matter?
Step 2A – Is the claim directed to a law of nature, natural phenomenon (product of nature), or an abstract idea? This is a two-prong inquiry:
Step 2A, prong 1 – Does the claim recite a law of nature, natural phenomenon, or an abstract idea?
Product of Nature Definition
When a law of nature or natural phenomenon is claimed as a physical product, the courts have often referred to the exception as a "product of nature". See Ass’n for Molecular Pathology v. Myriad Genetics, Inc., 569 U.S. 576, 580, 106 USPQ2d 1972, 1975 (2013); University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 758-59, 113 USPQ2d 1241, 1243 (Fed. Cir. 2014). As explained in those decisions, products of nature are considered to be an exception because they tie up the use of naturally occurring things, but they have been labeled as both laws of nature and natural phenomena. See Myriad Genetics, Inc., 569 U.S. at 590-91, 106 USPQ2d at 1979.
The Markedly Different Characteristics Analysis
The first step in the analysis is to select the appropriate counterpart to the nature-based product. When the nature-based product is derived from a naturally occurring thing, then the naturally occurring thing is the counterpart. See MPEP § 2106.04(c)(II)(A).
The second step in the analysis is to identify appropriate characteristics to compare. Appropriate characteristics must be possessed by the claimed product, because it is the claim that must define the invention to be patented. Cf. Roslin, 750 F.3d at 1338, 110 USPQ2d at 1673. See MPEP § 2106.04(c)(II)(B).
The final step in the markedly different characteristics analysis is to compare the characteristics of the claimed nature-based product to its naturally occurring counterpart in its natural state, in order to determine whether the characteristics of the claimed product are markedly different. See MPEP § 2106.04(c)(II)(C).
Step 2A, prong 2 – If the claim recites a judicial exception, does it recite additional elements that integrate the judicial exception into a practical application?
Limitations that are indicative of integration into a practical application include:
Improvements to the functioning of a computer, or to any other technology or technical field. See MPEP § 2106.05(a);
Applying the judicial exception with, or by use of, a particular machine. See MPEP § 2106.05(b);
Effecting a transformation or reduction of a particular article to a different state or thing. See MPEP § 2106.05(c);
Applying or using a judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition. See MPEP § 2106.05(d);
Applying or using the judicial exception in some other meaningful way beyond generally linking the use of the judicial exception to a particular technological environment, such that the claim as a whole is more than a drafting effort designed to monopolize the exception. See MPEP § 2106.05(e).
Step 2B – If the recited judicial exception is not integrated into a practical application, does the claim recite additional elements that amount to significantly different than the judicial exception such that they provide an inventive concept? This step includes evaluation of the same considerations under Step 2A, Prong 2, as well as two additional considerations:
Adding a specific limitation or combination of limitations that are not well-understood, routine, conventional activity in the field, which is indicative that an inventive concept may be present; and
Simply appending well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception, which is indicative that an inventive concept may not be present.
Analysis
Step 1: It must first be determined if the claim is to a statutory category and, if so, proceed to step 2A, prong 1.
The claims are directed to a pharmaceutical formulation comprising probiotic strain(s) and a pharmaceutically acceptable carrier, and fall within the statutory category of a composition of matter.
Step 2A, prong 1: Prong 1 requires the Examiner to evaluate whether the claim recites a judicial exception and, if so, proceed to prong 2.
Independent claim 1 recites that the pharmaceutical formulation comprises a “biotherapeutic” comprising either (i) a probiotic strain of Corynebacterium or (ii) a consortium of probiotics comprising at least one strain of Corynebacterium, and at least one pharmaceutically acceptable carrier.
Biotherapeutic: Given its plain meaning, the term “biotherapeutic” merely denotes that the formulation contains therapeutic compound(s) derived from living organisms, which includes the living organisms themselves. In the instant case, this term does not add any further structural limitation to the formulation beyond the recited probiotic strains themselves.
Probiotic: The term “probiotic” is defined in the instant specification as referring to a microorganism such as a bacteria or yeast that is associated with a positive effect for and/or confers an advantage to a subject (see pg. 9, para. [0037]). Unless otherwise specified by the claims, “probiotics” include microorganisms isolated from nature, which are natural products.
Corynebacterium: The specification states that Corynebacterium is a diverse bacterial genus that includes common residents of the upper respiratory tracts, skin and gastrointestinal tracts of humans and animals; although more than 150 species of Corynebacterium have been identified to date, the most common species isolated from the human respiratory tract are C. accolens, C. pseudodiphtheriticum, C. propinquum, C. striatum, and C. tuberculostearicum (see pg. 122, para. [0377]).
Consortium: The specification states that probiotic can comprise “a consortium” of bacterial strains from the same genus or species (e.g., Corynebacterium sp.) or a consortium of bacterial strains of different genera or species (see pg. 9, para. [0037]).
In view of the above, the “probiotic” or “consortium of probiotics” of the claim are disclosed as including naturally occurring bacteria (e.g., Corynebacterium) isolated from their environment (e.g., human/animal hosts), and are natural products.
Pharmaceutically acceptable carrier: The specification states that the term “pharmaceutically acceptable carrier” includes sterile aqueous solutions, examples of which include “water” (see pg. 13, para. [0047]). Hence, this limitation also includes natural products (e.g., water).
Markedly different characteristics: In view of the above, the minimal structure required by claim 1 may be met by one or more naturally-occurring bacteria in the presence of water. It is apparent that the bacteria and water are natural products which commonly occur together in their natural environment. Therefore, per MPEP 2106.04(c)(I), there is no need to perform the markedly difference characteristics analysis, because the limitations themselves, even in combination, are by definition directed to a naturally occurring product.
Thus, claim 1 is directed to the product of nature exception.
Claim 6, depending from claim 1, recites the further limitation, wherein the consortium of probiotics further comprises at least one strain from each of the bacterial genera, Dolosigranulum, Streptococcus, and Lactobacillus. In Example 2 of the specification, Corynebacterium, Dolosigranulum, Streptococcus, and Lactobacillus were identified in infant nasopharyngeal samples as part of Applicant’s study (see pg. 110, para. [0349], Table 4). Hence, similar to claim 1, the bacterial genera recited in claim 6 include naturally-occurring products (commensal bacteria), which have been found to occur together in their natural environment (the respiratory system). Thus, for the reasons discussed regarding claim 1, claim 6 is still directed to the judicial exception.
Claim 7, depending from claim 1, recites the further limitation, “wherein the strain or the at least one strain from the bacterial genus Corynebacterium comprises C. accolens… C. propinquum… C. pseudodiphtheriticum… C. striatum… C. tuberculostearicum… or any combination thereof”. As discussed regarding claim 1, the recited strains are among the most common species of Corynebacterium isolated from the human respiratory tract. Thus, claim 7 is still directed to the judicial exception.
Claim 8, depending from claim 1, recites the further limitation, wherein the biotherapeutic comprises at least 103 or up to at least 1012 CFUs of the probiotic(s). Here, the mere quantity of bacteria in in the composition is not sufficient, on its own, to distinguish it from a product of nature, particularly because higher quantities can be the natural result of bacterial growth, which is an inherent characteristic of the bacterium. Therefore, compared to a Corynebacterium strain occurring in its natural environment (i.e., the closest natural counterpart) any increase in quantity is, at best, an incidental change resulting from this inherent characteristic. See MPEP 2106.04(c)(II)(C). Thus, claim 8 is still directed to the judicial exception.
Claim 9, depending from claim 6, recites the further limitation, wherein the consortium comprises the strains of the four recited bacterial genera in a ratio of “1:0.01:0.01:0.01 to about “1:1:1:1”. In Example 2 of the specification, Corynebacterium, Dolosigranulum, Streptococcus, and Lactobacillus comprised 4.6%, 1.3%, 4.1%, and 1.7%, respectively, of the total bacterial genera identified in infant nasopharyngeal samples (see pg. 110, para. [0349], Table 4). Hence, the relative abundance of these bacterial genera in their natural environment is within the scope of the claim. Furthermore, as discussed regarding claim 8, the growth of the bacteria is an inherent characteristic of the bacteria in nature, and the relative abundance of the bacteria in the formulation is merely an incidental change resulting from this inherent characteristic. Thus, claim 9 is still directed to the judicial exception.
Step 2A, prong 2; Step 2B: In the instant case, claims 1 and 6-9 recite natural products (i.e., probiotics, carriers that include water) without any additional elements to evaluate under Step 2A, prong 2 or Step 2B. Hence, there are no elements beyond the naturally occurring product to integrate the judicial exception into a practical application or that amount to significantly more than the judicial exception.
Therefore, the claims are directed to natural products (Step 2A) and do not recite any additional elements that amount to significantly more (Step 2B).
In conclusion, claims 1 and 6-9 are directed to a judicial exception and do not qualify as eligible subject matter under 35 U.S.C. § 101.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1, 7-8, 16-17, 19-20, 24-25, 29-31, 33, 35, and 39-40 is/are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Zhou, et al. (US 2022/0202879 A1; cited on Form 892), effectively filed 12/15/2020, hereafter, “Zhou”.
Regarding claim 1, Zhou’s disclosure relates to methods and compositions utilizing upper-airway microbiota for diagnosing individuals at risk for asthma, and further to probiotic compositions and methods for treating asthma by administering microorganisms that are associated with decreased risk of asthma exacerbations (see Abstract). Zhou teaches a probiotic formulation for preventing, delaying or attenuating asthma exacerbations comprising a pharmaceutically acceptable unit dose of a probiotic composition comprising one or more isolated microorganisms selected from the genus Corynebacterium, genus Dolosigranulum, or a combination thereof, and a pharmaceutically acceptable carrier (see pg. 4, para. [0088]; pg. 5, para. [0108]). Hence, Zhou teaches all of the limitations of independent claim 1.
Regarding claim 7, Zhou teaches the microorganisms of genus Corynebacterium comprise microorganisms of Corynebacterium species C. pseudodiptheriticum or C. accolens (see pg. 5, para. [0109]).
Regarding claim 8, Zhou teaches that a suitable dose of the probiotic bacteria is from about 1x103 to about 1x1011 CFUs (see pg. 18, para. [0240]).
Regarding claim 16, Zhou teaches a method of treating an individual having early signs of loss of asthma control or asthma exacerbation comprising (1) detecting an altered amount, concentration, or proportion of a microorganism in a biological sample collected from an upper airway of the individual and (2) administering to the individual an agent that is effective to prevent or attenuate asthma exacerbations (see pg. 3, para. [0051]), wherein the agent is the probiotic composition previously described (see pg. 4, para. [0087]-[0088]). Zhou teaches that Streptococcus, Moraxella, and Haemophilus have a pathogenic role in asthma (see pg. 23, para. [0273]), and Corynebacterium and Dolosigranulum can inhibit the growth of Streptococcus by releasing antibacterial products that may also prevent nasal colonization with Streptococcus (see pg. 23, para. [0274]). Zhou teaches therapeutically effective amounts and suitable dosing for the probiotics in the formulation (see pg. 18, paras. [0239]-[0240]). Hence, Zhou teaches a method that promotes respiratory health in a subject (i.e., prevents and/or treats asthma, reduces pathogenic bacteria) comprising administering to a subject in need a formulation according to instant claim 1 in an amount effective to inhibit or prevent the growth of a pathogenic bacteria in the subject’s respiratory system.
Regarding claim 17, Zhou teaches the method comprising (1) detecting an altered amount, concentration, or proportion of a microorganism in a biological sample collected from an upper airway of the individual and (2) administering to the individual an agent that is effective to prevent or attenuate asthma exacerbations (see pg. 3, para. [0051]), wherein “the agent” is the probiotic composition previously described (see pg. 4, para. [0087]-[0088]). Zhou teaches the biological sample is a nasal blow sample (see pg. 2, para. [0043]). Hence, Zhou teaches the method comprising characterizing the microbiome of a biological sample, wherein the microbiome comprises the nasal microbiome, and administering to the subject in need a formulation according to instant claim 1 in an amount effective to inhibit or prevent the growth of a pathogenic bacteria in the subject’s respiratory system.
Regarding claim 19, Zhou teaches the detecting step comprises (a) acquiring a biological sample from an upper airway of an individual with asthma, (b) analyzing a plurality of microorganisms in the biological sample, and (c) determining an amount, concentration or proportion of a microorganism in the biological sample (see pg. 3, para. [0059]), wherein step (b) comprises analyzing a plurality of polynucleotides extracted from the biological sample (see pg. 3, para. [0062]) and sequencing a polynucleotide or a segment of a polynucleotide (see pg. 3, para. [0068]). Zhou’s Examples disclose this process which included “Statistical Analysis of the Microbiome Data” (see pg. 25, col. 1; paras. [0286]-[0287]), which reasonably includes the generation of sequence data (i.e., the data must be generated in order to be analyzed). Hence, Zhou teaches collecting a biological sample from the subject, extracting nucleic acid (i.e., polynucleotides) from the sample, and sequencing the extracted nucleic acid to generate sequence data.
Regarding claim 20, Zhou teaches the biological nasal blow sample is collected using a nasal swab (see pg. 12, [0174]).
Regarding claim 24, Zhou teaches the method wherein the microorganism detected in the biological sample is Moraxella or Streptococcus (see pg. 3, para. [0056]) which have a pathogenic role in asthma (see pg. 23, para. [0273]).
Regarding claim 25, Zhou teaches the method wherein the microorganism detected in the biological sample is Moraxella catarrhalis (see pg. 3, para. [0058]).
Regarding claim 29, Zhou teaches the microorganisms of genus Corynebacterium comprise microorganisms of Corynebacterium species C. pseudodiptheriticum or C. accolens (see pg. 5, para. [0109]).
Regarding claim 30, Zhou teaches that a suitable dose of the probiotic bacteria is from about 1x103 to about 1x1011 CFUs (see pg. 18, para. [0240]).
Regarding claim 31, Zhou teaches the method further comprising administering an antibacterial agent, wherein the antibacterial agent is a penicillin (see pg. 17, paras. [0220]-[0223]).
Regarding claim 33, Zhou teaches the microorganisms of the genera Corynebacterium and Dolosigranulum are capable of inhibiting the growth and/or colonization of the upper airway of the individual by microorganisms of the genera Staphylococcus, Streptococcus, and Moraxella (see pg. 5, para. [0099]). Zhou teaches that bacteria colonizing the upper airways exist in a competitive state, and competitive colonization may be one of the factors by which commensal bacteria provide protection against pathogen colonization and overgrowth (see pg. 23, para. [0274]). Further, Corynebacterium and Dolosigranulum can inhibit and/or prevent the growth and/or colonization of Streptococcus, and the relative abundance of Corynebacterium and Dolosigranulum may serve as potential microbiome markers for respiratory health (see pgs. 23-24, para. [0274]). Hence, the administering of these probiotics is reasonably suggested by Zhou’s disclosure to have the effect of decreasing the relative abundance of the pathogenic bacteria.
Furthermore, where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). "Products of identical chemical composition can not have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). In this case, the further functional limitation of the claim is directed to an inherent property that does not affect the structure or steps of the claimed invention. As Zhou teaches the same process of administering the same composition as the instant claims, the effects and properties of administering said composition are presumed to be inherent and the claimed method is anticipated. See MPEP 2112.01 which states:
Under the principles of inherency, if a prior art device, in its normal and usual operation, would necessarily perform the method claimed, then the method claimed will be considered to be anticipated by the prior art device. When the prior art device is the same as a device described in the specification for carrying out the claimed method, it can be assumed the device will inherently perform the claimed process. In re King, 801 F.2d 1324, 231 USPQ 136 (Fed. Cir. 1986)
Regarding claim 35, Zhou teaches the composition can be administered by a dosing schedule or dosing regimen, such as, at least once a day or at least twice a day (see pg. 19, para. [0246]). Hence, Zhou teaches the method comprising repeating the administration.
Regarding claim 39, Zhou’s study revealed that changes in the upper respiratory tract are associated with events in the lower respiratory tract, and multiple studies have highlighted the relevance of the upper airway microbiota as a surrogate for the lung microbiota (see pg. 24, para. [0278]). Furthermore, the prevention of the pathogenic bacteria spreading and/or colonizing to a different part of the subject’s respiratory system is reasonably interpreted to be an effect of administering the formulation which does not require any further structure or method step. As Zhou teaches the same process of administering the same composition as the instant claims, the effects and properties of administering said composition are presumed to be inherent and the claimed method is anticipated. See discussion regarding claim 33 above.
Regarding claim 40, Zhou teaches the composition is formulated for nasal administration (see pg. 5, para. [0113]) and is administered to the nasal cavity (see pgs. 17-18, para. [0230]).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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.
Claim(s) 6 and 28 is/are rejected under 35 U.S.C. 103 as being unpatentable over Zhou as applied to claims 1, 7-8, 16-17, 19-20, 24-25, 29-31, 33, 35 and 39-40 above, and further in view of De Grandi, et al. (cited on Form 892), hereafter, “Grandi”.
Regarding claim 6, Zhou teaches the probiotic formulation comprising probiotic strains of Corynebacterium and Dolosigranulum, and a pharmaceutically acceptable carrier, as discussed above. Zhou also teaches the method further comprising administering a second probiotic composition comprising a bacterium from the genus Lactobacillus (see pg. 17, para. [0218]). Zhou teaches that airway microbiota dominated by Corynebacterium and Dolosigranulum are associated with favorable clinical outcomes compared to microbiota dominated by more pathogenic Staphylococcus and Moraxella bacteria (see pg. 1, para. [0006]), and increased abundance of Staphylococcus aureus is indicative of an increased risk of asthma exacerbations (see pg. 20, para. [0249]).
Zhou does not teach the composition comprising at least one strain from the bacterial genus Streptococcus.
Grandi teaches that changes in the bacterial composition of nasal microbiota may alter the host’s susceptibility to several infectious diseases, and a strong and significant decrease in Staphylococcus aureus abundance was detected immediately after the bacterial administration of Streptococcus salivarius 24SMBc and Streptococcus oralis 89a (see Abstract). Grandi teaches that this reduction could be due to a potential ability of the two strains to displace the pathogens or to predominate the unwanted microbial species as previously described for lactic acid bacteria (e.g., Lactobacilli) that exert antiadhesive and antimicrobial effects against S. aureus strains or other opportunistic pathogens (see pg. 1223, col. 2, para. 2). Grandi teaches that the nasal microbiota is a complex microbial community, composed of several different genera of aerobic and anaerobic microorganisms such as Staphylococcus spp., Corynebacterium spp., and Propionibacterium spp. (see pg. 1219, col. 1). Grandi teaches that several studies demonstrated how commensal alpha-hemolytic streptococci could be used to recover the normal nasopharyngeal flora in children with recurrent otitis media, and these microorganisms may not only restore the balance between beneficial commensal bacteria and pathogenic species but may also prevent development of antimicrobial resistance due to the intensive use of antibiotics in the treatment of nasal diseases (see pg. 1219, col. 2, para. 1). Grandi discloses a probiotic product based on the combination of Streptococcus salivarius 24Mbc and Streptococcus oralis 89a, developed for direct nasal administration through a vaporizer for the prophylaxis and treatment of chronic and recurrent infections of the upper airways (see pg. 1219, col. 2, para. 2). Grandi teaches that the reduction of potential harmful bacteria demonstrated in the study is an important feature of the two probiotic streptococcal strains and indicates a promising use for future applications in the clinical field (see pg. 1226, col. 1, para. 1).
It would have been obvious at the time of filing for a person of ordinary skill in the art to have arrived at the claimed invention by combining the teachings of Zhou and Grandi, because both references teach compositions comprising beneficial nasal probiotics that are useful for the prophylaxis and treatment of pathogenic infections of the respiratory system. One would have also recognized that both references teach that beneficial probiotics, such as Corynebacterium and Lactobacillus, have the ability to inhibit and displace disease-causing bacteria, such as Staphylococcus aureus, and teach that the nasal administration of beneficial probiotics (i.e., Corynebacterium, Dolosigranulum, Lactobacillus, and alpha-hemolytic strains of Streptococcus) can effectively prevent or treat diseases of the respiratory system. Hence, one would have been particularly motivated to provide a composition which combined these desired effects. One would have also recognized that each element (i.e., probiotic strain) could have been combined by known methods, and that in combination, each element merely performs the same function as it does separately (i.e., inhibits and/or displaces pathogenic bacteria). As such, one would have recognized that the results of the combination to have been predictable and there to have been a reasonable expectation of success when applying the combination. Hence, the combination would have been readily apparent and deemed to be a mere (A) combining of prior art elements according to known methods to yield predictable results (see MPEP 2143(I): Rationales to support rejections under 35 U.S.C. 103).
Regarding claim 28, Zhou teaches all the elements of claim 16, as discussed under 35 U.S.C. 102, and the further limitations of the claim are the same as claim 6 above. Hence, the claim is obvious for the same reasons discussed regarding claims 6 and 16.
Claim(s) 9 is/are rejected under 35 U.S.C. 103 as being unpatentable over Zhou and Grandi as applied to claims 1, 6-8, 16-17, 19-20, 24-25, 28-31, 33, 35 and 39-40 above, and further in view of Harburger, et al. (US Patent No. 12,329,792 B2; cited on Form 892), effectively filed 05/28/2020, hereafter, “Harburger”.
Regarding claim 9, Zhou and Grandi teach compositions comprising beneficial bacteria, such as Corynebacterium, Dolosigranulum, Lactobacillus, and alpha-hemolytic strains of Streptococcus, to prevent and treat respiratory infections by pathogenic bacteria, such as Staphylococcus aureus, and Zhou teaches that a higher relative abundance of Corynebacterium and Dolosigranulum and a lower relative abundance of the pathogenic bacteria is associated with favorable clinical outcomes in subjects having asthma, as discussed above.
Zhou and Grandi do not explicitly teach wherein the probiotic strains are in a ratio of about 1:0.01:0.01:0.01 to about 1:1:1:1.
Harburger teaches compositions and methods comprising live Corynebacterium and/or
Dolosigranulum pigrum bacteria for the modulation, restoration and/or promotion of the microbiome in the upper respiratory tract of a subject, including the nasal cavity, to promote health (see Abstract). Harburger teaches that probiotic bacteria provide a therapeutic opportunity for addressing microbiome imbalance and disease related conditions, and there is a need for forms of intervention which promote an improved microbiome environment in the upper respiratory tract, in particular the nasal cavity, for the treatment and prevention of conditions in the nasal cavity as well as in systems linked to the upper respiratory tract by a shared mucosal network, such as the lower respiratory tract and central nervous system (see col. 1, lines 21-27). Harburger teaches that lower respiratory tract conditions for treatment or prevention by the administration of the composition includes asthma (see col. 10, lines 52-55). Harburger teaches that the bacteria selected for the composition are used to control, treat, reduce, eliminate, and/or prevent pathogenic colonization by an organism in a subject, and the composition may be administered for delivery to the upper respiratory tract, including the nasal cavity (see col. 4, lines 33-35). Harburger teaches that when administered to a subject, the bacterial population reduces or eliminates colonization in the respiratory tract of pathogenic bacteria, such as Staphylococcus aureus (see col. 6, lines 45-50). Harburger teaches that the composition comprises a bacterial population of up to 4 or more strains comprising at least one strain of Corynebacterium and at least one strain of Dolosigranulum, and such strains may be present in equal amounts or varied amounts (see col. 6, lines 9-15, 29-33).
Hence, Harburger’s disclosure is closely related to solving the same problem as Zhou using a particularly similar means (i.e., administering Corynebacterium and Dolosigranulum to inhibit pathogens of the respiratory system to treat and prevent lower respiratory conditions, such as asthma). Further, Harburger’s disclosure of providing up to 4 or more strains “in equal amounts” is equivalent to the claimed limitation of providing the strains in a ratio of “about 1:1:1:1”. In view of the instant specification, the term “about” means a value falling within a range that is ± 10% of the stated value (see instant specification at pg. 8, para. [0030]). Hence, Harburger’s disclosure of providing the strains “in equal amounts” is within the claimed range, and the ratio of “1:1:1:1” would have been prima facie obvious in view of Harburger.
Therefore, it would have been obvious at the time of filing for a person of ordinary skill in the art to have arrived at the claimed invention by combining the teachings of Zhou, Grandi and Harburger because each reference teaches compositions comprising beneficial nasal probiotics that are useful for the prophylaxis and treatment of pathogenic infections of the respiratory system. One would have also recognized that each reference teaches that beneficial probiotics, such as Corynebacterium, Dolosigranulum, Lactobacillus, and alpha-hemolytic strains of Streptococcus, have the ability to inhibit and displace disease-causing bacteria, such as Staphylococcus aureus, and further teach that the nasal administration of such probiotics can effectively prevent or treat diseases of the respiratory system, such as asthma. Hence, one would have been particularly motivated to have provided a composition which combined these desired effects. One would have also recognized that each element (i.e., probiotic strain) could have been combined by known methods, and that in combination, each element merely performs the same function as it does separately (i.e., inhibits and/or displaces pathogenic bacteria). As such, one would have recognized that the results of the combination to have been predictable and there to have been a reasonable expectation of success when applying the combination. Hence, the combination would have been readily apparent and deemed to be a mere (A) combining of prior art elements according to known methods to yield predictable results (see MPEP 2143(I): Rationales to support rejections under 35 U.S.C. 103).
Claim(s) 21 is/are rejected under 35 U.S.C. 103 as being unpatentable over Zhou as applied to claims 1, 7-8, 16-17, 19-20, 24-25, 29-31, 33, 35 and 39-40 above, and further in view of Walters et al. (cited on Form 892), hereafter, “Walters”.
Regarding claim 21, Zhou teaches collecting a biological sample from the subject, extracting nucleic acid (i.e., polynucleotides) from the sample, and sequencing the extracted nucleic acid to generate sequence data, as discussed above. Zhou discloses that standard Illumina sequencing protocol was followed, using a pair of primers to amplify the 16S rRNA gene (see pg. 25, para. [0282]), and the sequence data was analyzed using taxonomic classification (“taxa”) to characterize the bacterial microbiota (see pg. 25, paras. [0282]-[0285]). Hence, Zhou teaches the method further comprising analyzing the sequence data using taxonomic classification, wherein taxonomic classification comprises performing PCR amplification using a pair of primers.
Zhou does not explicitly teach the method wherein the primers have (i) the sequence set forth in SEQ ID NO: 01 and SEQ ID NO: 02, (ii) the sequence set forth in SEQ ID NO: 03 and in SEQ ID NO: 04, or (iii) the sequence set forth in SEQ ID NO: 05 and in SEQ ID NO: 06.
Walters teaches that designing primers for PCR-based taxonomic surveys that amplify a broad range of phylotypes in varied community samples is a difficult challenge, and the comparability of data sets amplified with varied primers requires attention (see “Abstract”). Walter’s study demonstrated that two recently modified primer pairs that target taxonomically discriminatory regions of bacterial and fungal genomic DNA do not introduce new biases when used on a variety of sample types, from soil to human skin, confirming the utility of these primers for maintaining currently recommended microbiome research techniques as the state of the art (See “Importance”). Walters teaches that the 515f-806r bacterial/archaeal primer pair, traditionally used by the Earth Microbiome Project, was recently shown to be biased against both the Crenarchaeota/Thaumarchaeota, important environmental archaea, and the SAR11 clade, which is abundant in aquatic bacteria. Walters teaches that the 515f/806r 16S rRNA
gene primer pair, first designed for use with the Illumina platform, have been previously modified to reduce these biases (see pg. 2, para. 2). Walters study showed that the modified 515f/806r primer pairs do not introduce detrimental biases compared to the original constructs in nonaquatic environments and were highly concordant with the original 515f/806r and 515f/926r results (see pg. 7, para. 2). The primer pairs used in Walters study are shown in Table 1 (see pg. 2), as shown below (arrows added by examiner):
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Here, the modified 515f/806r primer pairs of Walters are identical to instant SEQ ID NOs 1 and 2, respectively, as shown in the following alignments:
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123
584
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114
583
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It would have been obvious at the time of filing for a person of ordinary skill to have arrived at the claimed invention by substituting the primers taught by Zhou with those taught by Walters, because Walters teaches the modified primers amplify a broad range of phylotypes in varied community samples and reduce detrimental biases compared to the original constructs. Furthermore, it is apparent in view of Walter’s disclosure, that these primer constructs were known in the art at the time of filing, and Walter’s study merely confirms the utility of these primers for use in microbiome research. As Walters discloses these primers amplify a broad range of phylotypes (i.e., from aquatic to non-aquatic environments, from soil to human skin) without detrimental biases, a person of skill would have recognized that these primers could have been substituted with the primers taught by Zhou, and the results of making this substitution would have been predictable. As the use of these primers have been shown to yield predictable and reliable results in PCR-based taxonomic surveys before the time of filing, one would have had a reasonable expectation of success when applying the substitution. Hence, the combination would have been readily apparent and deemed to be a mere (B) simple substitution of one known element for another to obtain predictable results (see MPEP 2143(I): Rationales to support rejections under 35 U.S.C. 103).
Conclusion
No claims are allowed.
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/DENNIS IGNATIUS ARMATO JR/Examiner, Art Unit 1651
/MELENIE L GORDON/Supervisory Patent Examiner, Art Unit 1651