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 .
Priority
Acknowledgment is made of Applicant's claim for priority from U.S. Provisional Application No. 62/988,152, filed on March 11, 2020.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on July 28, 2025 has been entered.
Response to Amendment
By Applicant’s amendment filed on July 28, 2025 claims 1, 8, 10, 11, 16, 17 have been amended, claim 9 has been cancelled, and new claims 22 and 23 have been added. Claims 18-21 are withdrawn.
It is noted that new claim 23 is dependent upon claim 2. However since claim 23 is the same as claim 2, it is presumed that claim 23 should be dependent upon claim 22. Thus for the sake of compact prosecution, claim 23 is being interpreted as being dependent upon claim 22.
Newly submitted claims 22 and 23 are directed to an invention that is independent or distinct from the invention originally claimed for the following reasons: new claims 22 and 23 are drawn to a different method than claims 1-8 and 10-17 since new claims 22-23 recite in step c that the subject has received at least one dose of methotrexate and at least one dose of folic acid, whereas claim 1 recites only administering methotrexate.
Since applicant has received an action on the merits for the originally presented invention, this invention has been constructively elected by original presentation for prosecution on the merits. Accordingly, claims 22 and 23 are withdrawn from consideration as being directed to a non-elected invention. See 37 CFR 1.142(b) and MPEP § 821.03.
To preserve a right to petition, the reply to this action must distinctly and specifically point out supposed errors in the restriction requirement. Otherwise, the election shall be treated as a final election without traverse. Traversal must be timely. Failure to timely traverse the requirement will result in the loss of right to petition under 37 CFR 1.144. If claims are subsequently added, applicant must indicate which of the subsequently added claims are readable upon the elected invention.
Should applicant traverse on the ground that the inventions are not patentably distinct, applicant should submit evidence or identify such evidence now of record showing the inventions to be obvious variants or clearly admit on the record that this is the case. In either instance, if the examiner finds one of the inventions unpatentable over the prior art, the evidence or admission may be used in a rejection under 35 U.S.C. 103 or pre-AIA 35 U.S.C. 103(a) of the other invention.
Accordingly, claims 1-8 and 10-17 are currently presented for examination.
Response to Arguments
Due to Applicant’s amendments to claims 11, 16 and 17, the previous rejection under 35 USC 112(b) is hereby withdrawn.
Applicant's arguments filed July 28, 2025 with respect to the rejection under 35 USC 103 have been fully considered but they are not persuasive.
Applicant argues that claim 1 has been amended to recite that Bacteroidetes is one of (or the only) bacterial phylum that is analyzed and Zhang does not recite the element, “wherein the at least one bacterial phylum is Bacteroidetes...” nor does Zhang recite the element “f) administering a medication other than MTX if the abundance of step d) is equal to or more than the abundance of step b).” Applicant argues that Zhang merely reports comparative data for cohorts (pre- and post-treatment), but does not teach an individualized, intra-patient comparison to guide subsequent medication decisions as claimed. Applicant argues that Zhang shows changes in specific taxa before/after DMARDs, but it does not propose a therapeutic pathway where the detection of a specific abundance change in a given phylum triggers a change in medication regimen in that subject.
Applicant argues one would not be led to the presently claimed invention from Zhang because at the time of the filing of the priority document, the Bacteroidetes abundance in gut microbiome samples was not known as a marker of response to methotrexate treatment in RA patients and nothing in Zhang would lead one to look specifically at the abundance of the Bacteroidetes phylum in the gut microbiome as a biomarker to response to methotrexate. Applicant argues that even though Zhang mentions members of the Bacteroidetes phylum, as shown in Fig. 2A-B, they are shown to be enriched in the control group of oral (Fig. 2A) and both the RA and control groups of the salivary (Fig. 2B) samples and the microbiomes in the oral cavity and colon are highly distinct, making it difficult to extrapolate these findings to a gut microbial biomarker. Applicant argues that one would learn from Zhang that Bacteroidetes is biologically relevant but would not be led to comparing the total abundance of the Bacteroidetes phylum in gut microbiome samples as indicative of methotrexate treatment responsivity. Applicant further argues that Frank does not cure the deficiencies of Zhang.
These arguments are found not persuasive since Zhang et al. specifically teaches to investigate the gut microbiome in RA patients, we carried out metagenomic shotgun sequencing of 212 fecal samples (77 treatment naive individuals with RA and 80 unrelated healthy controls; 17 treatment-naive individuals with RA paired with 17 healthy relatives; and 21 samples from DMARD-treated individuals with RA) (Supplementary Tables 1 and 2) (page 896). Thus Zhang et al. specifically teaches obtaining a gut sample prior to treatment with DMARD and after treatment with DMARD to determine the changes in gut microbiome in RA patients. Supplementary Figure 3 of Zhang et al. specifically demonstrates gut MLGs which were determined in the samples which specifically include bacteria from Bacteriodetes phylum. Zhang demonstrates that compared to control RA gut is enriched with bacteria from Bacteriodetes phylum (supplementary figure 3). Zhang further teaches that the abundance of RA-enriched MLGs such as C. asparagiforme and Bacteroides sp. was positively correlated with titers of immunoglobulin A (IgA), and that of an unclassified Lactobacillus sp. (most likely L. salivarius; Supplementary Table 4) positively correlated with titers of the major serum immunoglobulin, IgG (Supplementary Fig. 4). Thus Zhang specifically teaches determining the abundance of bacteria from the phylum Bacteriodetes as claimed. Moreover, Zhang specifically demonstrates in supplementary figure 13 that in the gut, bacteria from the phylum Bacteriodetes as claimed was reduced in RA patients with moderate or good response to DMARD treatment compared to those with no improvement (see also pages 902-903 and Figure 6a).
Thus prior to the effective filing date of the instant claims, as taught by Zhang et al. it was known in the art that gut microbial dysbiosis is detectable in rheumatoid arthritis (RA) and is associated with clinical indices (page 896). Moreover, prior to the effective filing date of the instant claims, it was known in the art that disease-modifying antirheumatic drugs (DMARDs) including methotrexate could influence the abundance of bacterial phylum in rheumatoid arthritis. Zhang et al. specifically teaches that DMARD treatment partially restores a healthy RA microbiome which is consistent with treatment improvement (page 902). Zhang et al. specifically teaches to examine whether DMARD treatment restores a healthy microbiome, the relative abundance of control and RA gut and oral MLGs was compared before and after treatment (for 3 months in 34 individuals and for other time periods for six fecal samples) (Supplementary Tables 1 and 2) (page 902). Zhang et al. teaches that cross-validated random forest models based on gut, dental or salivary MLGs in before-treatment samples were able to distinguish patients who showed good or moderate improvement from patients who showed no improvement after DMARD therapy (Fig. 6d, Supplementary Fig. 14 and Supplementary Table 22) (page 902).
Zhang et al. teaches that most of the treated RA patients received methotrexate (MTX), glycosides of the traditional Chinese medicinal component Tripterygium wilfordii (thunder god vine) (T2) or both (MTX + T2) for DMARD treatment (Supplementary Tables 1 and 22) (page 904). Zhang et al. specifically teaches that MLGs enriched in RA gut such as H. filiformis and Bacteroides sp. were reduced after treatment with MTX or MTX + T2 (Supplementary Fig. 13b) (page 904). Supplementary table 22 specifically teaches that some patients were treated with MTX alone, T2 alone, or a combination of MTX and T2 and supplementary figure 13 b specifically demonstrates the reduction of bacteria after treatment with MTX alone. Zhang et al. teaches that gut, dental or salivary MLGs in before-treatment samples were able to distinguish patients who showed good or moderate improvement from patients who showed no improvement after DMARD therapy, including MTX alone (see Supplementary Fig. 14 and Supplementary Table 22).
Thus Zhang et al. specifically teaches the following: gut microbial dysbiosis is detectable in rheumatoid arthritis (RA); treating rheumatoid arthritis in a subject comprising the administration of methotrexate; bacteria from phylum Bacteriodetes in before-treatment samples were able to distinguish patients who showed good or moderate improvement from patients who showed no improvement after methotrexate therapy; methotrexate can restore a healthy microbiome by reducing the abundance of bacteria from phylum Bacteriodetes in patients treated for rheumatoid arthritis.
A reference is good not only for what it teaches by direct anticipation but also for what one of ordinary skill in the art might reasonably infer from the teachings. (In re Opprecht 12 USPQ 2d 1235, 1236 (Fed Cir. 1989); In re Bode 193 USPQ 12 (CCPA) 1976). In the instant case, a skilled artisan would reasonably infer from the teachings of Zhang et al. that since gut microbial dysbiosis is known in rheumatoid arthritis (RA) and that RA represents a state of chronic inflammation that might be provoked or aggravated by the overgrowth of pathogenic bacteria or a lack of immune-modulating commensal bacteria, and methotrexate administration is known to at least partially restore a healthy microbiome in RA patients that respond to methotrexate, it would have been obvious to administer methotrexate to RA patients if the abundance of at least one bacterial phyla including phylum Bacteriodetes, after MTX treatment is less than the abundance of at least one bacterial phyla, including phylum Bacteriodetes, prior to treatment which indicates responsiveness to MTX treatment. One of ordinary skill in the art would, therefore, have been motivated to administer a medication other than MTX if it was determined that no effect on the abundance of bacteria was detected which would indicate that the RA patient is not responsive to MTX based on the teachings of Zhang et al.
It must be remembered that "[w]hen a patent simply arranges old elements with each performing the same function it had been known to perform and yields no more than one would expect ....the combination is obvious". KSR v. Teleflex, 127 S.Ct. 1727, 1740 (2007) (quoting Sakraida v. A.G. Pro, 425 U.S. 273, 282 (1976)). Consistent with this reasoning, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the instant claims to have selected the various combinations of features claimed from within the prior art disclosure specifically, administering methotrexate for the treatment of rheumatoid arthritis if it has been determined that methotrexate restores a healthy microbiome, which includes reducing unhealthy bacteria, which would indicate that the RA patient is responsive to MTX to arrive at the instantly claimed subject matter.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Applicant’s argument with respect to the Frank reference is found not persuasive since the teachings of Frank were provided to teach therapies other than MTX in which an artisan would consider if MTX was determined ineffective. Accordingly, prior to the effective filing date of the instant claims, it would have been obvious to a person of ordinary skill in the art to administer another known compound for the treatment of RA if the patient does not respond to methotrexate treatment. A person of ordinary skill in the art would have been motivated to administer any one of Non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen or naproxen; steroids such as prednisone; disease-modifying anti-rheumatic drugs (DMARDs) such as Hydroxychloroquine, Sulfasalazine, Azathioprine and Lefludomide; biologics such as Remicade®, Enbrel®, and Humira®; and Janus kinase (JAK) inhibitors as taught in Frank as an alternative to methotrexate with a reasonable expectation of success.
Applicant further argues that a person of ordinary skill in the art would not be motivated to combine the teachings of Zhang with the teachings of Jovel because Zhang states that using 16S rRNA is not sufficient to identify gut microbial disease markers.
These arguments are found not persuasive since Zhang does not state that 16S rRNA is not sufficient to identify gut microbial disease markers as argued by Applicant. However, Zhang specifically teaches that the results determined therein partly confirm and extend the results of previous studies based on 16S rRNA sequencing (page 896). Thus Zhang actually teaches that similar results can be achieved utilizing 16S rRNA and does not teach away as argued by Applicant.
Thus, for these reasons the previous rejection under 35 USC 103 is hereby maintained and reproduced below.
This action is FINAL.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1 and 3-17 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et. (Nature Medicine, Volume 21, Number 8, August 2015, pages 895-906) in view of Frank (Arthritis Health, (2016) 5 Types of Medication that Treat Rheumatoid Arthritis, https://www.arthritis-health.com/types/rheumatoid/5-types-medication-treat-rheumatoid-arthritis-ra).
Claims 1 and 3-17 of the instant application claim a method of treating rheumatoid arthritis (RA) in a subject comprising the steps of: a. obtaining a first microbiome sample from the subject, wherein said subject has not received methotrexate, b. determining the abundance of at least one bacterial phyla in said sample; c. obtaining a second microbiome sample from the subject, wherein said subject has received at least one dose of methotrexate, and d. determining the abundance of at least one bacterial phyla in said sample; e. comparing the abundance of step (b) with the abundance of step (d); and f. administering methotrexate (MTX) if the abundance of step (d) is less than the abundance of step (b), or administering a medication other than MTX if the abundance of step (d) is equal to or more than the abundance of step (b).
Zhang et al. (page 896) teaches that gut microbial dysbiosis is detectable in rheumatoid arthritis (RA) and is associated with clinical indices. Zhang et al. teaches that in order to investigate the gut microbiome in RA patients, metagenomic shotgun sequencing of 212 fecal samples (77 treatment naive individuals with RA and 80 unrelated healthy controls; 17 treatment-naive individuals with RA paired with 17 healthy relatives; and 21 samples from DMARD-treated individuals with RA) was carried out and the data was then integrated into an existing gut microbial reference-gene catalog to obtain a set of 5.9 million genes, which allowed for saturation mapping of the sequencing reads (80.3% ± 2.3%, mean ± s.d.). Zhang et al. teaches that gut microbial diversity and richness were similar between the 77 treatment-naive individuals with RA and 80 unrelated healthy controls. Zhang et al. teaches to delineate features of the RA-associated gut microbiome, 117,219 gene markers that were differentially enriched in RA patients were identified versus controls (Wilcoxon rank-sum test, false discovery rate (FDR) < 0.3) and the genes were clustered into metagenomic linkage groups (MLGs) on the basis of their correlated abundance variation among samples. The 88 MLGs that contained at least 100 genes (Supplementary Fig. 3 and Supplementary Table 4) separated RA-enriched and control-enriched MLGs along the vector for RA status in canonical correspondence analysis (CCA) (Supplementary Fig. 4), confirming that they were associated mainly with RA status, rather than with other complicating factors. A cluster containing Veillonella and Haemophilus strains (Spearman’s correlation coefficient > 0.3), along with other MLGs including Klebsiella pneumoniae, Bifidobacterium bifidum, Sutterella wadsworthensis and Megamonas hypermegale, were enriched in the healthy controls compared with the RA subjects (Supplementary Fig. 3). In contrast, the RA-enriched MLGs formed a large cluster including Clostridium asparagiforme, Gordonibacter pamelaeae, Eggerthella lenta and Lachnospiraceae bacterium, as well as small clusters or single MLGs containing strains such as Bifidobacterium dentium, Lactobacillus sp. and Ruminococcus lactaris. A few control MLGs negatively correlated with RA MLGs (e.g., K. pneumoniae and Bacteroides sp., B. bifidum and R. lactaris) (Supplementary Fig. 3), suggesting an antagonistic or mutually exclusive relationship. See page 896 first column.
Zhang et al. teaches that the RA gut was enriched in Gram-positive bacteria and depleted of Gram-negative bacteria, including some Proteobacteria and Gram negative Firmicutes of the Veillonellaceae family (Supplementary Fig. 3). A few phylogenetically related strains showed different directions of enrichment. For instance, Con-1511 (most closely related to Bacteroides plebeius) was enriched in controls, whereas a Bacteroides sp. (most closely related to Bacteroides sp. 20_3) was enriched in RA patients (Supplementary Fig. 3 and Supplementary Table 4). Zhang et al. teaches that these results partly confirm and extend the results of previous studies based on 16S rRNA sequencing (Supplementary Table 5). See page 896 first column. Zhang et al. teaches determining the abundance of bacteria phyla including Bacteroidetes, Actinobacteria, Firmicutes, Proteobacteria, Fusobacteria, and Spirochaetes, and including family Coriobacteriaceae, Prevotellaceae, Porphyromonadaceae, Lachnospiraceae, Streptococcaceae, and Erysipelotrichaceae (Figure 2 pages 898-899).
Zhang et al. teaches the abundance of RA-enriched MLGs such as C. asparagiforme and Bacteroides sp. was positively correlated with titers of immunoglobulin A (IgA), and that of an unclassified Lactobacillus sp. (most likely L. salivarius; Supplementary Table 4) positively correlated with titers of the major serum immunoglobulin, IgG (Supplementary Fig. 4). A positive correlation between RA-2166 (which is related to Enterococcus faecalis; Supplementary Table 4) and platelet count (Supplementary Fig. 6) was detected, which is consistent with prior reports showing that E. faecalis binds platelets. Other species include Bacteroides vulgatus (Supplementary Table 4). See second column page 896.
Zhang et al. further teaches to examine whether DMARD treatment restores a healthy microbiome, the relative abundance of control and RA gut and oral MLGs was compared before and after treatment (for 3 months in 34 individuals and for other time periods for six fecal samples) (Supplementary Tables 1 and 2). Consistent with results from the RA classifiers, more dental and salivary MLGs showed significant changes in abundance than did gut MLGs (P < 0.05, Wilcoxon rank-sum test; Fig. 6 and Supplementary Fig. 13). In the dental plaques, amounts of RA-24803 were decreased after DMARD therapy, especially in patients who showed good or moderate improvement after treatment compared to those with no improvement (P < 0.05, Wilcoxon rank-sum test; Fig. 6b,c), according to the European League Against Rheumatism (EULAR) response criteria based on DAS28 reduction. MLGs enriched in healthy control dental samples, including Prevotella maculosa, increased in RA patients after treatment, especially in those who showed good or moderate improvement. Among the control MLGs that were differentially enriched in dental samples of patients with good, moderate or no improvement after DMARD therapy were MLGs (unclassified Aggregatibacter sp., Con-3223 and Con-6189) that negatively correlated with CRP, anti-CCP or RF, implying clinically relevant improvement in the dental microbiome. See page 902.
Zhang et al. teaches that cross-validated random forest models based on gut, dental or salivary MLGs in before-treatment samples were able to distinguish patients who showed good or moderate improvement from patients who showed no improvement after DMARD therapy (dental: AUC, 0.881; specificity, 1.000; sensitivity, 0.667; Fig. 6d, Supplementary Fig. 14 and Supplementary Table 22). Gut MLGs used in the improvement classifiers included Con-5303, Con-3144 and Holdemania filifor-mis, which correlated with dental and salivary MLGs (Fig. 4 and Supplementary Table 4). Oral MLGs included in the classifiers, including Veillonella spp., also correlated with gut MLGs (Fig. 4 and Supplementary Tables 10 and 11). Fecal, dental and salivary samples from RA patients who showed improvement contained a greater number of virulence factors (according to the virulence factor database) than did those from patients with no improvement, and the dental and salivary control samples had more virulence factors than the RA patient samples (Supplementary Fig. 15 and Supplementary Tables 23–25). See pages 902-903.
Zhang et al. teaches in summary, DMARD treatment partially modified the RA-associated microbiome, and the associated MLGs might facilitate the prediction and evaluation of treatment effects. Zhang et al. teaches that most of the treated RA patients received methotrexate (MTX), glycosides of the traditional Chinese medicinal component Tripterygium wilfordii (thunder god vine) (T2) or both (MTX + T2) for DMARD treatment (Supplementary Tables 1 and 22). MLGs enriched in RA gut such as H. filiformis and Bacteroides sp. were reduced to a greater extent after treatment with T2 than after treatment with MTX or MTX + T2 (Supplementary Fig. 13b). MLGs enriched in control dental samples, including P. intermedia, were more abundant in patients treated with MTX + T2 than in those treated with T2 alone or MTX alone, whereas Veillonella sp. and RA-8489, enriched in RA saliva samples, were reduced to a greater extent in patients treated with T2 or with MTX + T2 (Fig. 6f and Supplementary Fig. 13d). These data suggest that distinct DMARDs modulate the gut and oral microbiome differently, although differences among RA patients remain likely. See pages 903-904.
The teachings of Zhang et al. identified compositional and functional alterations in RA-associated gut and oral microbiomes that were partly relieved by DMARD treatment. Gut and oral MLGs correlated with each other and with clinical indices such as CRP, anti-CCP and RF, and they permitted preliminary classification of RA subjects. The dental and salivary microbiomes were altered, and these could be sampled easily at clinical visits or by the patients themselves. The comprehensive survey of the gut and oral microbiomes in individuals with RA supports the notion that RA represents a state of chronic inflammation that might be provoked or aggravated by the overgrowth of pathogenic bacteria or a lack of immune-modulating commensal bacteria (Supplementary Note). See page 904.
Zhang et al. teaches that treatment was performed with MTX-based DMARDs as part of a single-blind randomized trial. 97% of the patients received MTX alone (7.5 mg weekly (QW) initially, increased to 15 mg (maximum of 0.3 mg/kg) QW from week 4 on; supplemented with 10 mg QW folate), T2 alone (20 mg TID), or MTX + T2 (same doses as when administered individually) (Supplementary Table 1). Other drugs used on the remaining patients included leflunomide, prednisolone, hydroxychloroquine and etanercept, which were not compared because of the small sample size (Supplementary Table 1). Reduction in DAS28-ESR after treatment was classified as good, moderate or no improvement according to the EULAR response criteria. See Methods section.
Thus Zhang et al. investigates the influence of the microbiome on determining treatment outcomes in response to MTX using shotgun metagenomics to characterize the salivary, dental, and fecal microbiome of treatment-naive RA patients before and after the use of MTX. Differentially-abundant species were identified in baseline samples from patients that were responding well, moderately or not at all (based on DAS28 reduction) and it was found that MTX changed the composition of the fecal microbiome. Thus Zhang et al. teaches that MTX may act either by decreasing the abundance of disease-associated bacteria or by restoring a healthy microbiome. This study also generated predictive models using the microbiome data collected, which were able to differentiate between good and poor responders. These observations provide evidence that microbiome-based variables are important in determining whether an RA patient responds well or poorly to treatment with MTX.
Zhang et al. does not specifically teach administering methotrexate (MTX) if the abundance of step (d) is less than the abundance of step (b), or administering a medication other than MTX if the abundance of step (d) is equal to or more than the abundance of step (b).
However, a reference is good not only for what it teaches by direct anticipation but also for what one of ordinary skill in the art might reasonably infer from the teachings. (In re Opprecht 12 USPQ 2d 1235, 1236 (Fed Cir. 1989); In re Bode 193 USPQ 12 (CCPA) 1976). In the instant case, a skilled artisan would reasonably infer from the teachings of Zhang et al. that since gut microbial dysbiosis is known in rheumatoid arthritis (RA) and that RA represents a state of chronic inflammation that might be provoked or aggravated by the overgrowth of pathogenic bacteria or a lack of immune-modulating commensal bacteria, and methotrexate administration is known to at least partially restore a healthy microbiome in RA patients that respond to methotrexate, it would have been obvious to administer methotrexate to RA patients if the abundance of at least one bacterial phyla after MTX treatment is less than the abundance of at least one bacterial phyla prior to treatment which indicates responsiveness to MTX treatment. One of ordinary skill in the art would, therefore, have been motivated to administer a medication other than MTX if the abundance of step (b) is equal to or more than the abundance of step (a) which would indicate that the RA patient is not responsive to MTX based on the teachings of Zhang et al.
Frank teaches that medications for RA typically fall into five categories: Non-steroidal anti-inflammatory drugs (NSAIDs); steroids; disease-modifying anti-rheumatic drugs (DMARDs); biologics; and Janus kinase (JAK) inhibitors (page 1). Frank teaches that most people with RA are advised to take a non-steroidal anti-inflammatory drug to decrease pain and inflammation. NSAIDs are sold over-the-counter, under such names as Advil (ibuprofen) and Aleve (naproxen), as well as by prescription, under names such as Mobic and Celebrex. Frank teaches that fast-acting steroids, such as prednisone, are particularly useful during initial treatment, before other RA medications have had a chance to take effect (often 12 weeks or more). Frank teaches that Disease-modifying antirheumatic drugs (DMARDs) are used to slow or stop rheumatoid arthritis by suppressing the immune system. The generic names for commonly used DMARDs include: Hydroxychloroquine, Methotrexate, Sulfasalazine, Azathioprine and Lefludomide. Frank teaches that biologic response modifiers, is technically a subset of DMARDs and may be used with traditional DMARDs or as an alternative to them. Biologics fall into four categories: Tumor necrosis factor (TNF) inhibitors; Interleukin (IL) inhibitors; B-cells inhibitors; and T-cells inhibitors. These medications are administered by injection or infusion and examples include Remicade, Enbrel, and Humira.
Accordingly, prior to the effective filing date of the instant claims, it would have been obvious to a person of ordinary skill in the art to administer another known compound for the treatment of RA if the patient does not respond to methotrexate treatment. A person of ordinary skill in the art would have been motivated to administer any one of Non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen or naproxen; steroids such as prednisone; disease-modifying anti-rheumatic drugs (DMARDs) such as Hydroxychloroquine, Sulfasalazine, Azathioprine and Lefludomide; biologics such as Remicade®, Enbrel®, and Humira®; and Janus kinase (JAK) inhibitors as an alternative to methotrexate with a reasonable expectation of success.
Claims 4 and 5 are rendered obvious since Zhang et al. teaches to examine whether DMARD treatment restores a healthy microbiome, the relative abundance of control and RA gut and oral MLGs was compared before and after treatment (for 3 months in 34 individuals and for other time periods for six fecal samples). Zhang et al. teaches that MTX was administered once weekly (QW). Thus Zhang et al. teaches that the second sample was received after 12 weeks which renders obvious claim 5 which recites 1, 2, 3, 4, or more weeks. Although Zhang et al. teaches that the subject received more than 5 doses of MTX prior to obtaining the second sample, claim 4 is rendered obvious since it is within the skill of an ordinary artisan to determine an appropriate regimen in order to obtain optimal results. One would have been motivated to evaluate the patient prior to 12 weeks of MTX treatment to determine treatment efficacy earlier. Thus in the absence of secondary considerations such as unexpected results, claim 4 is rendered obvious in view of the cited prior art.
Thus the cited claims of the instant application are rendered obvious in view of the cited prior art teachings.
Claim 2 is rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. (Nature Medicine, Volume 21, Number 8, August 2015, pages 895-906) in view of Frank (Arthritis Health, (2016) 5 Types of Medication that Treat Rheumatoid Arthritis, https://www.arthritis-health.com/types/rheumatoid/5-types-medication-treat-rheumatoid-arthritis-ra) as applied to claims 1 and 3-17 above and further in view of Jovel et al. (2016, Characterization of the Gut Microbiome Using 16S or Shotgun Metagenomics. Front. Microbiol. 7:459).
Claim 2 of the instant application claims the abundance is measured by 16S RNA copy number per gram sample.
Zhang et al. in view of Frank is as set forth above.
Zhang et al. does not teach the abundance is measured by 16S RNA copy number per gram sample rather Zhang et al. teaches the abundance is measured by metagenomic shotgun sequencing of fecal samples.
Jovel et al. teaches that the advent of next generation sequencing (NGS) has enabled investigations of the gut microbiome with unprecedented resolution and throughput and this has stimulated the development of sophisticated bioinformatics tools to analyze the massive amounts of data generated (abstract). Jovel et al. teaches the two main approaches for analyzing the microbiome are 16S ribosomal RNA (rRNA) gene amplicons and shotgun metagenomics (abstract). Jovel et al. teaches the choice of shotgun or 16S approaches for microbiome analyses is usually dictated by the nature of the studies being conducted (page 10). Jovel et al. teaches that 16S is well suited for analysis of large number of samples, i.e., multiple patients, longitudinal studies, etc. but offers limited taxonomical and functional resolution. Jovel et al. teaches that shotgun metagenomics on the other hand is usually more expensive but offers increased resolution, enabling a more specific taxonomic and functional classification of sequences as well as the discovery of new bacterial genes and genomes (page 10).
Accordingly, prior to the effective filing date of the instant claims, it would have been obvious to a person of ordinary skill in the art to examine the microbiome sample using 16 S RNA copy number as claimed in claim 2 since Jovel et al. teaches that 16 S is an obvious alternative to the more expensive shotgun metagenomics taught in Zhang et al. Thus substituting the 16 S method for the shotgun metagenomics taught in Zhang et al. would have been seen as an obvious alternative to yield predictable results and within the purview of an artisan practicing the invention. Thus claim 2 of the instant application is rendered obvious in view of the cited prior art teachings.
Conclusion
Claims 1-8 and 10-17 are rejected. Claim 9 is cancelled. Claims 18-23 are withdrawn. No claims are allowed.
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KARA R. MCMILLIAN whose telephone number is (571)270-5236. The examiner can normally be reached Tuesday-Friday 12:00 PM-6:00 PM.
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/KARA R. MCMILLIAN/Primary Examiner, Art Unit 1623
KRM