The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
This office action is in response to Applicants’ amendments/remarks received January 21, 2026.
Rejections and/or objections not reiterated from previous office actions are hereby withdrawn.
Claims 2-3, 5-15, 17-19, 22, 24-26, 28-32, 34-35, 37-43, 45-46, 49-54, 56-58, 60-64 are canceled. Claims 1, 4, 16, 20-21, 23, 27, 33, 36, 44, 47-48, 55, 59 are under consideration.
Priority: This Application has a provisional Application PRO 62/843,849 (filing date of May 6, 2019). This Application is a 371 of PCT/US2020/031429 (filing date of May 5, 2020). The certified copy of the Priority Application acknowledging provisional Application PRO 62/843,849 and 371 of PCT/US2020/031429 was received (receipt date of November 2, 2021).
Objections and Rejections
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.
Claim 4 is 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.
Claim 4 recites the subject is a transplant recipient. Claim 4 is dependent on claim 1, where claim 1 recites the subject is a recipient of allogeneic hematopoietic stem cell transplantation. Therefore, it is not clear how claim 4 further limits claim 1. Further clarification and/or correction is requested.
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, 4, 16, 20-21, 23, 27, 33, 36, 44, 47-48, 55, 59 are rejected under 35 U.S.C. 103 as being unpatentable over Bristol et al. (US 20160101058; IDS 11.02.21, previously cited) in view of Bristol II (WO 2016/033327A1; IDS 04.22.22, previously cited), Callejas-Días et al. (2014 Curr Hematol Malig Rep 9: 85-90; previously cited), and Fredricks (2019 J Clin Invest 129(5): 1808-1817, published May 1, 2019; IDS 11.02.21, previously cited).
Bristol et al. disclose modified release formulations comprising a beta-lactamase which releases a substantial amount of the beta-lactamase in the intestines (abstract). Bristol et al. disclose the approach for avoiding or rebalancing the ecological balance of normal intestine microbiota using beta-lactamases to maintain a normal intestinal microbiota and preventing its overgrowth with potentially pathogenic microorganisms (at least paragraph 0008). Bristol et al. disclose these improved beta-lactamases find uses in a number of therapies, including for preventing and treating Clostridium difficile infection (CDI) and/or a Clostridium difficile-associated disease or other antibiotic-induced adverse effects in the GI tract; for example, the beta-lactamases find use in allowing a patient to undergo antibiotic therapy while protected against diseases that could result from excess antibiotics negatively affecting the microbiome; such use does not interfere with the systemic utility of the antibiotic, rather, the beta-lactamases remove excess antibiotic that may populate parts of the GI tract and, in doing so, prevent the disruption of the microbiota linked to the various disease states (at least paragraph 0011). Bristol et al. disclose methods for preventing and treating CDI and/or a Clostridium difficile-associated disease comprising administering an effective amount of a modified-release formulation of a beta-lactamase agent to a patient undergoing therapy with a primary antibiotic, the antibiotic is ceftriaxone, cefotaxime, piperacillin, etc. (at least paragraphs 0012, 0140). Bristol et al. disclose the beta-lactamases comprise the amino acid sequence having of SEQ ID NO:1, also known as P3A (at least paragraphs 0037, 0038), where SEQ ID NO: 1 appears to have 100% sequence identity with instant SEQ ID NO: 1. Bristol et al. disclose the modified-release formulation could be administered with additional therapeutic agent or combined into a single-release formulation (at least paragraph 0129). The methods disclosed in the teachings of Bristol et al. for treating CDI and/or a Clostridium difficile-associated disease comprising administering an effective amount of a modified-release formulation of a beta-lactamase agent to a patient prevents and treats colonization, expansion of colonization or monodomination and/or infection by Clostridium difficile which are known to be drug resistant microorganisms. Bristol et al. disclose that in various embodiments, the subjects include, but are not limited to, subjects at particular risk for a microbiome-mediated disorder, such as by way of non-limiting example, those undergoing treatment or having recently undergone treatment with an antibiotic; for example, the subject may have taken an antibiotic during the past 30 days or so and/or have an immune system that is weak (at least paragraph 0143), where the antibiotic is a cephalosporin, such as ceftriaxone, cefepime (at least paragraph 0144). Bristol et al. do not explicitly teach CDI is associated with graft-versus-host disease.
Bristol II discloses antibiotic medical treatments, which are needed to treat certain aspects of disease, can induce disruption in the microbiome, including the GI tract, and lead to further disease; for instance, administered beta-lactams like ampicillin, ceftriaxone, cefoperazone, piperacillin, that are not eliminated are residual unabsorbed beta-lactams in the intestinal tract and may cause an undesirable effect on the ecological balance of normal intestinal microbiota resulting in CDI, antibiotic-associated diarrhea, etc. (at least p. 2, first paragraph). Bristol II also discloses the therapeutic use of beta-lactamases for rebalancing the ecological balance of normal intestinal microbiota by inactivating excreted or unabsorbed antibiotics, thereby maintaining a normal intestinal microbiota (at least p. 2, second paragraph). Bristol II discloses in some embodiments, the beta-lactamases and/or pharmaceutical compositions comprise the amino acid sequence having of SEQ ID NO:5, also known as P3A (page 29, lines 3-10 and 11-18; claims 12 and 19(c)), where SEQ ID NO: 15 has 100% sequence identity with instant SEQ ID NO: 1 (see the May 21, 2024 non-final office action p. 28-29).
Callejas-Díaz et al. disclose CDI, the most common cause of hospital-acquired diarrhea, is very frequent after hematopoietic stem cell transplantation (HSCT) (at least p. 85). Callejas-Diaz et al. disclose allo-HSCT recipients may be exposed to more of the classic risk factors for CDI (e.g., antibiotics, proton-pump inhibitors) for longer periods of time, but they are also given immunosuppressive agents, and may develop graft versus host disease (GvHD), which can cause watery diarrhea (at least p. 85). Callejas-Díaz et al. disclose CDI typically occurs after the first month after HSCT and it may result in worsening of bowel GvHD after allo-HSCT (at least p. 85). Callejas-Díaz et al. disclose that current evidence suggests C. difficile disease may increase the risk of GvHD (at least p. 85).
Fredricks discloses that graft-versus-host disease (GvHD) is a common complication of allogeneic hematopoietic cell transplantation (HCT) (at least p. 1808). Fredricks discloses that there is compelling evidence that the gut microbiota is associated with risk of GvHD (at least p. 1808). Fredricks discloses that patients undergoing HCT typically receive systemic broad-spectrum antibiotics intended to prevent bacterial infections; however, these disrupt gut microbiota (at least p. 1809 Fig. 1). Fredricks discloses microbiota-linked interventions for GvHD include administering beta-lactamase following antibiotic, including ceftriaxone (a cephalosporin), treatment to patients (at least p. 1813-1814, also Table 2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the references and arrive at the claimed method of reducing the severity of GvHD, in a subject in need thereof, comprising administering an effective amount of a beta-lactamase agent, wherein the beta-lactamase agent has an amino acid sequence of instant SEQ ID NO: 1, wherein the subject is an allo-HSCT recipient and wherein the subject is being or has been administered an IV beta-lactam antibiotic, wherein the IV beta-lactam antibiotic is a cephalosporin such as cefepime (instant claims 1, 4, 16, 20-21, 23, 27, 33, 36, 44, 47-48, 55, 59). The motivation to do so is given by the prior art. Bristol et al. disclose methods for treating and reducing CDI and/or Clostridium difficile-associated diseases comprising administering an effective amount of a modified-release formulation of a beta-lactamase agent to a patient undergoing therapy with an antibiotic to treat colonization and expansion of C. difficile, where subjects include, but are not limited to, subjects at particular risk for a microbiome-mediated disorder, such as by way of non-limiting example, those undergoing treatment or having recently undergone treatment with an antibiotic; for example, the subject may have taken an antibiotic during the past 30 days or so and/or have an immune system that is weak (at least paragraph 0143), where the antibiotic is a cephalosporin, such as ceftriaxone, cefepime (at least paragraph 0144). Bristol II discloses antibiotic medical treatments disrupt the microbiome and discloses the therapeutic benefits of beta-lactamases, including P3A, comprising the amino acid sequence having of SEQ ID NO:5 (and having 100% sequence identity to instant SEQ ID NO: 1) for rebalancing the ecological balance of normal intestinal microbiota by inactivating excreted or unabsorbed antibiotics, thereby maintaining a normal intestinal microbiota. Callejas-Díaz et al. disclose that allo-HSCT recipients receive antibiotics and that CDI is very frequent after allo-HSCT and that current evidence suggests C. difficile disease may increase the risk of GvHD. Fredricks discloses that patients undergoing allo-HCT also typically receive systemic broad-spectrum antibiotics intended to prevent bacterial infections; however, these disrupt gut microbiota and that there is compelling evidence that the gut microbiota is associated with risk of GvHD. Fredricks discloses microbiota-linked interventions for GvHD include administering beta-lactamase following antibiotic, including a cephalosporin, treatment to patients. Therefore, one of ordinary skill would have reasonable motivation to administer the P3A beta-lactamases having 100% sequence identity with instant SEQ ID NO: 1 of Bristol et al./Bristol II in the method for treating CDI and/or Clostridium difficile-associated diseases in a patient that has been administered an IV beta-lactam antibiotic of Bristol et al. and further where the patient being administered the P3A beta-lactamase is an allo-HSCT patient having received antibiotic therapy, where the antibiotic is a known cephalosporin such as cefepime and thereby is also treated for the reduced severity of GvHD, as noted in Fredricks/ Callejas-Díaz et al. One of ordinary skill would have a reasonable expectation of success because the prior art discloses administering beta-lactamase to subjects having recently undergone treatment with an antibiotic; where the subject may have taken an antibiotic during the past 30 days or so and/or have an immune system that is weak, to thereby maintain a normal intestinal microbiota, and for treating conditions that result in an undesirable effect of the normal intestinal microbiota caused by antibiotic treatment, such as CDI, Clostridium difficile-associated diseases, and GvHD.
Further, regarding the limitation “wherein the patient has been administered an IV beta-lactam antibiotic selected from piperacillin, cefepime, meropenem” (instant claims 1, 33), Fredericks discloses microbiota-linked interventions for GvHD include administering beta-lactamase following antibiotic, including ceftriaxone (a cephalosporin), treatment to patients (at least p. 1813-1814, also Table 2). Bristol et al. disclose that in various embodiments, the subjects include, but are not limited to, subjects at particular risk for a microbiome-mediated disorder, such as by way of non-limiting example, those undergoing treatment or having recently undergone treatment with an antibiotic; for example, the subject may have taken an antibiotic during the past 30 days or so and/or have an immune system that is weak (at least paragraph 0143), where the antibiotic is a cephalosporin, such as ceftriaxone (third generation), cefepime (fourth generation) (at least paragraph 0144). Therefore, it would have been obvious to arrive at the recited antibiotic selected from a cephalosporin such as cefepime.
Regarding the limitations, “wherein new colonization within the intestinal microbiome of the subject is prevented, expansion of colonization within the intestinal microbiome of the subject is prevented, and/or monodomination of the intestinal microbiome is prevented” (instant claims 1, 16, 33, 44, 47-48), as noted above, Bristol et al. disclose the approach for rebalancing the ecological balance of normal intestine microbiota using beta-lactamases, including P3A, to maintain a normal intestinal microbiota and preventing its overgrowth with potentially pathogenic microorganisms (at least paragraphs 0008, 0037-0038) and Bristol II discloses the therapeutic benefits of beta-lactamases, including P3A, comprising the amino acid sequence having of SEQ ID NO:5 (and having 100% sequence identity to instant SEQ ID NO: 1) for rebalancing the ecological balance of normal intestinal microbiota by inactivating excreted or unabsorbed antibiotics, thereby maintaining a normal intestinal microbiota (at least p. 2, p. 29). Since the prior art disclose administering beta-lactamases that are structurally the same as the recited beta-lactamases, for treating the same patient population, it would follow that the P3A beta-lactamase disclosed in the prior art comprises the properties of reducing the incidence of colonization, expansion of colonization, or monodomination and/or infection by one or more multi-drug resistant pathogens in a subject (instant claims 1, 16, 33, 44, 47-48).
Regarding instant claim 20, Bristol et al. disclose an “effective amount” provides for reduction in the rate of pathogenesis of a disorder of interest (at least paragraph 0219) and Bristol II also discloses “effective amount” provides for reduction in the rate of pathogenesis of a disorder of interest (at least p. 42). Therefore, it would be obvious that the P3A beta-lactamase disclosed in the prior art for treating CDI and/or a Clostridium difficile-associated diseases in a patient that has been administered an IV beta-lactam antibiotic of Bristol et al. and where the patient being administered the beta-lactamase is a transplant patient and also treated for reduced severity of GvHD, as noted in Fredricks/ Callejas-Díaz et al., will reduce the dosing of therapeutic agents to treat GvHD.
Regarding instant claim 21, Bristol et al. has disclosed that the subjects include those undergoing treatment or having recently undergone treatment with an antibiotic; for example, the subject may have taken an antibiotic during the past 30 days or so and/or have an immune system that is weak (at least paragraph 0143). Callejas-Díaz et al. disclose transplant patients are also treated with immunosuppressive agents (at least p. 85) and Fredricks discloses immunosuppressive therapies for treating GvHD (at least p. 1810).
Regarding instant claims 23, 27, 55, 59, Bristol et al. disclose release of the P3A beta-lactamase formulation in the intestine (at least example 9) and where the P3A beta-lactamase formulation has an enteric coating (at least example 9).
Regarding instant claim 36, Callejas-Díaz et al. disclose the patients having CDI after HSCT include hospitalized patients and having worsening GvHD (at least p. 85).
Reply: Applicants’ amendments/remarks have been considered but they are not persuasive. The reasons for maintaining the 103 rejection are the same as previously noted and are incorporated herein.
Applicants assert that Bristol et al. describe the treatment of a CDI using beta-lactamase, in particular P2A, P3A, or P4A. Applicants assert that Bristol et al. is silent with respect to transplantation and/or GvHD. Applicants assert that importantly, CDI and GvHD are distinct diseases having different causes and mechanisms.
Applicants’ remarks are not persuasive. As previously noted, the deficiency of Bristol et al. to not teach GvHD is remedied by Callejas-Díaz et al. and/or Fredricks. As noted above, Bristol et al. has disclosed methods for treating and reducing CDI and/or a Clostridium difficile-associated diseases comprising administering an effective amount of a modified-release formulation of a P3A beta-lactamase agent to a patient undergoing therapy with a primary antibiotic to treat colonization and expansion of C. difficile (see 103 rejection above).
Bristol et al. disclose these improved beta-lactamases find uses in a number of therapies, including for preventing and treating CDI and/or a Clostridium difficile-associated disease or other antibiotic-induced adverse effects in the GI tract; for example, the beta-lactamases find use in allowing a patient to undergo antibiotic therapy while protected against diseases that could result from excess antibiotics negatively affecting the microbiome; such use does not interfere with the systemic utility of the antibiotic, rather, the beta-lactamases remove excess antibiotic that may populate parts of the GI tract and, in doing so, prevent the disruption of the microbiota linked to the various disease states (at least paragraph 0011).
Bristol et al. further disclose that in various embodiments, the subjects include, but are not limited to, subjects at particular risk for a microbiome-mediated disorder, such as by way of non-limiting example, those undergoing treatment or having recently undergone treatment with an antibiotic; for example, the subject may have taken an antibiotic during the past 30 days or so and/or have an immune system that is weak (at least paragraph 0143), where the antibiotic is a cephalosporin, such as ceftriaxone, cefepime (at least paragraph 0144).
Therefore, Bristol et al. fairly contemplate treating and reducing not only CDI, but also Clostridium difficile-associated diseases by administering the P3A beta-lactamase agent to patients having been administered an antibiotic and having a weak immune system.
Callejas-Diaz et al. disclose allo-HSCT recipients may be exposed to more of the classic risk factors for CDI (e.g., antibiotics, proton-pump inhibitors) for longer periods of time, but they are also given immunosuppressive agents, and may develop GvHD, which can cause watery diarrhea (at least p. 85). Callejas-Díaz et al. disclose CDI typically occurs after the first month after HSCT and it may result in worsening of bowel GvHD after allo-HSCT (at least p. 85). Callejas-Díaz et al. disclose that current evidence suggests C. difficile disease may increase the risk of GvHD (at least p. 85).
Fredricks discloses that GvHD is a common complication of allogeneic hematopoietic cell transplantation (HCT) (at least p. 1808). Fredricks discloses that there is compelling evidence that the gut microbiota is associated with risk of GvHD (at least p. 1808). Fredricks discloses that patients undergoing HCT typically receive systemic broad-spectrum antibiotics intended to prevent bacterial infections; however, these disrupt gut microbiota (at least p. 1809 Fig. 1). Fredricks discloses microbiota-linked interventions for GvHD include administering beta-lactamase following antibiotic, including ceftriaxone (a cephalosporin), treatment to patients (at least p. 1813-1814, also Table 2). Fredericks discloses patients undergoing allo-HCT have a weak immune system and are subject to radical changes in their microbiota while receiving antibiotics and recovering from conditioning-related tissue damage (at least p. 1814).
Therefore, one of ordinary skill would have reasonable motivation to administer the P3A beta-lactamases having 100% sequence identity with instant SEQ ID NO: 1 of Bristol et al./Bristol II in the method for treating CDI and/or Clostridium difficile-associated diseases in a patient that has been administered an IV beta-lactam antibiotic of Bristol et al. and further where the patient being administered the P3A beta-lactamase is an allo-HSCT patient having received antibiotic therapy, where the antibiotic is a known cephalosporin such as cefepime and thereby is also treated for the reduced severity of GvHD, as noted in Fredricks/ Callejas-Díaz et al. One of ordinary skill would have a reasonable expectation of success because the prior art discloses administering beta-lactamase to subjects having recently undergone treatment with an antibiotic; where the subject may have taken an antibiotic during the past 30 days or so and/or have an immune system that is weak, to thereby maintain a normal intestinal microbiota, and for treating conditions that result in an undesirable effect of the normal intestinal microbiota caused by antibiotic treatment, such as CDI, Clostridium difficile-associated diseases, and GvHD.
Regarding Applicants’ remarks that CDI and GvHD are distinct diseases having different causes and mechanisms, the remarks are not persuasive. As previously noted, while CDI and GvHD are different disorders, it is recognized in the prior art that both disorders are associated by disruption of the gut microbiota. Bristol et al. disclose disruption of the gut microbiome by antibiotic treatments and that residual unabsorbed beta-lactams can cause an undesirable effect on the ecological balance of the normal intestinal microbiota resulting in for example CDI (at least paragraph 0007). Fredricks discloses that there is compelling evidence that the gut microbiota is associated with risk of GvHD (at least p. 1808, 1810-1811) and that patients undergoing HCT typically receive systemic broad-spectrum antibiotics intended to prevent bacterial infections; however, these disrupt gut microbiota (at least p. 1809 Fig. 1). This is further acknowledged in the prior art by Bhutani et al. (2019 Bone Marrow Transplantation 54(1): 164-167; IDS 10.19.23), which disclose that the other mechanism linking the two diagnoses may be decreased/altered microbial diversity, which is seen both in patients with CDI and with GI GvHD (p. 166).
Therefore, the prior art has recognized that both CDI and GvHD are associated by gut microbiota disruption and/or are linked by having a decreased/altered microbial diversity.
Therefore, Applicants’ remarks that CDI and GvHD are distinct diseases having different causes and mechanisms are not found persuasive.
Applicants assert that treatments for CDI and GvHD are different and that it is not standard of care to treat the two diseases in the same way or with a single treatment and thus, a person of ordinary skill would have no reasonable expectation of success that a treatment for CDI would work to treat to GvHD, or vice versa.
Applicants’ remarks are not persuasive. As noted above, Bristol et al. disclose that the beta-lactamases find uses in other therapies, besides just CDI. At paragraph 0011, Bristol et al. disclose that these improved beta-lactamases find uses in a number of therapies, including Clostridium difficile-associated disease or other antibiotic-induced adverse effects in the GI tract; for example, the beta-lactamases find use in allowing a patient to undergo antibiotic therapy while protected against diseases that could result from excess antibiotics negatively affecting the microbiome; such use does not interfere with the systemic utility of the antibiotic, rather, the beta-lactamases remove excess antibiotic that may populate parts of the GI tract and, in doing so, prevent the disruption of the microbiota linked to the various disease states.
Bristol et al. further disclose that the subjects include, but are not limited to, subjects at particular risk for a microbiome-mediated disorder, such as by way of non-limiting example, those undergoing treatment or having recently undergone treatment with an antibiotic; for example, the subject may have taken an antibiotic during the past 30 days or so and/or have an immune system that is weak (at least paragraph 0143), where the antibiotic is a cephalosporin, such as ceftriaxone, cefepime (at least paragraph 0144).
Therefore, Bristol et al. fairly disclose the P3A beta-lactamase agent as a treatment for not only CDI, but also for patients undergoing antibiotic therapy having been administered an antibiotic and having a weak immune system.
Fredericks discloses patients undergoing allo-HCT lack a functioning immune system and are subject to radical changes in their microbiota while receiving antibiotics and recovering from conditioning-related tissue damage (at least p. 1814). Therefore, Fredericks discloses that allo-HCT patients are patients that undergo treatment with an antibiotic and have a weakened immune system, which are the same types of patients or subjects that Bristol et al. have identified are at particular risk for a microbiome-related disorder and can be treated with the P3A beta-lactamase agent.
Fredricks has also disclosed microbiota-linked interventions for GvHD include administering beta-lactamase following antibiotic, including ceftriaxone (a cephalosporin), treatment to patients (at least p. 1813-1814, also Table 2).
Bristol et al. has also disclosed that the antibiotic is a cephalosporin, such as ceftriaxone (third generation), cefepime (fourth generation) (at least paragraph 0144).
Therefore, one of ordinary skill would have a reasonable expectation of success that the P3A beta-lactamases having 100% sequence identity with instant SEQ ID NO: 1 of Bristol et al./Bristol II can be successfully administered to an allo-HSCT patient having received antibiotic therapy, where the antibiotic is a known cephalosporin and thereby is also treated for the reduced severity of GvHD, as noted in Fredricks/ Callejas-Díaz et al. because the prior art discloses administering beta-lactamase to subjects having recently undergone treatment with an antibiotic; where the subject may have taken an antibiotic during the past 30 days or so and/or have an immune system that is weak, to thereby maintain a normal intestinal microbiota, and for treating conditions that result in an undesirable effect of the normal intestinal microbiota caused by antibiotic treatment, such as CDI, Clostridium difficile-associated diseases, and GvHD.
Therefore, Applicants’ remarks that a person of ordinary skill would have no reasonable expectation of success that a treatment for CDI would work to treat to GvHD, or vice versa are not found persuasive.
Applicants assert that Bristol II teaches methods for production of beta-lactamases using E. coli cells and like Bristol et al., Bristol II is silent with respect to transplantation and/or GvHD.
Applicants’ remarks are not persuasive. Bristol II, like Bristol et al., discloses the therapeutic benefits of beta-lactamases, including P3A, comprising the amino acid sequence having of SEQ ID NO:5 (and having 100% sequence identity to instant SEQ ID NO: 1) for rebalancing the ecological balance of normal intestinal microbiota by inactivating excreted or unabsorbed antibiotics, thereby maintaining a normal intestinal microbiota (at least p. 2, p. 29). The deficiency of Bristol II to not teach GvHD is remedied by Callejas-Díaz et al. and/or Fredricks for the reasons already noted above.
Regarding Applicants’ remarks that Bristol II is silent on prevention or reduction of new colonization within the intestinal microbiome, the remarks are not persuasive. Since the cited prior art disclose administering beta-lactamases that are structurally the same as the recited beta-lactamases, and for treating the same patient population, it would follow that the P3A beta-lactamase disclosed in the prior art comprises the properties of reducing the incidence of colonization, expansion of colonization, or monodomination and/or infection by one or more multi-drug resistant pathogens in a subject or patient.
Applicants assert that Callejas-Díaz et al. examine the relationship between CDI and GvHD in HSCT. Applicants assert that Callejas-Díaz et al. do not assert a causal relationship between CDI infections and GvHD.
Applicants’ remarks are not persuasive. Callejas-Díaz et al. disclose that CDI, the most common cause of hospital-acquired diarrhea, is very frequent after HSCT (at least p. 85). As also noted by Applicants, Callejas-Díaz et al. disclose that CDI may result in worsening of GvHD after allo-HSCT and that current evidence suggests a reciprocal effect by which GvHD may increase the risk of CDI and C. difficile disease may increase the risk of GvHD (p. 85). Therefore, Callejas-Díaz et al. fairly disclose that CDI is associated with GvHD and vice versa. This is also confirmed and supported in the prior art by Bhutani et al., which confirm the findings of increased risk of GI GvHD in patients who develop CDI in the post-transplant period (p. 166) and that CDI causes worsening tissue injury and inflammation in the gut thus increasing the risk for GI GvHD (p. 166).
Regarding Applicants’ remarks that Callejas-Díaz et al. do not teach or suggest a beta-lactamase, the remarks are not persuasive. Callejas-Díaz et al. is cited as a 103 reference with at least Bristol et al. and Bristol II, which disclose the therapeutic benefits of beta-lactamases, including P3A, comprising the amino acid sequence having of SEQ ID NO:5 (and having 100% sequence identity to instant SEQ ID NO: 1) for treating C. difficile associated diseases and rebalancing the ecological balance of normal intestinal microbiota by inactivating excreted or unabsorbed antibiotics, thereby maintaining a normal intestinal microbiota (Bristol et al. 0012, 0140; Bristol II at least p. 2, p. 29). Therefore, one of ordinary skill would have a reasonable expectation of success of administering beta-lactamase to maintain a normal intestinal microbiota for treating conditions that result in an undesirable effect of the normal intestinal microbiota caused by antibiotic treatment, where such conditions include Clostridium difficile-associated diseases such as GvHD and/or CDI.
Applicants assert that Fredricks is a review article that discusses the complexities of GvHD. Applicants assert that Fredricks (p. 1812) highlights that there was conflicting literature about the benefit of gut bacteria on GvHD. Applicants assert that importantly, the studies highlighted on Table 2 of Fredricks and referred to in the office action were not related to GvHD and were instead related to CDI. Applicants submit exhibit A and B, corresponding to citations 59 and 58 in Fredricks.
Applicants’ remarks are not persuasive. Fredricks actually discloses that animal and human studies provide compelling evidence that the gut microbiota is associated with risk of GvHD (at least p. 1808). In Fig. 1, Fredricks discloses models of intestinal environments affecting GvHD development (p. 1809). Fredricks discloses that patients undergoing HCT typically receive systemic broad-spectrum antibiotics intended to prevent bacterial infections during neutropenia; these disrupt gut microbiota and reduce bacterial diversity (at least p. 1809 Fig. 1A). Fredricks discloses that GvHD pathogenesis occurs as a result of intestinal dysbiosis arising from antibiotics, including reduced bacterial diversity, etc. (at least p. 1809 Fig. 1B). Fredricks discloses that absence of GvHD is noted by preservation of the gut microbiota (at least p. 1809 Fig. 1C). Therefore, Fredricks fairly discloses that GvHD is associated with disrupted gut microbiota and that preserving and maintaining balance of the gut microbiota reduces GvHD. This is also further supported in the prior art by Bhutani et al., which disclose a mechanism linking the two diagnoses may be decreased/altered microbial diversity, which is seen both in patients with CDI and with GI GvHD (p. 166), and thus, reducing the incidence of CDI may help reduce the incidence of GI GvHD (p. 166).
Regarding Applicants’ remarks that the studies highlighted in Table 2 of Fredricks are not related to GvHD and are instead related to CDI, the remarks are not persuasive. As noted above, Fredricks has established that the gut microbiota is associated with the risk of GvHD and that disruption of the gut microbiota by antibiotics increases GvHD. Bristol et al. has disclosed that disruption of the gut microbiome by antibiotic treatments and that residual unabsorbed beta-lactams can cause an undesirable effect on the ecological balance of the normal intestinal microbiota resulting in CDI (Bristol et al. at least paragraph 0007). Therefore, it is recognized in the prior art that both disorders are associated by disruption of the gut microbiota.
Further, the studies in citations 59 and 58 referenced in Fredricks, and noted by Applicants, all present data that support that beta-lactamase maintains the balance of the gut microbiome and degrade excess antibiotic that is excreted into the small intestine.
Since Fredricks has established that the gut microbiota is associated with the risk of GvHD and that disruption of the gut microbiota by antibiotics increases GvHD, the clinical data on microbiota-linked interventions for GvHD disclosed in Table 2 of Fredricks, including administering beta-lactamase following antibiotic, including ceftriaxone, treatment to patients (p. 1813-1814, also Table 2) clearly relates to GvHD, in addition to CDI, because the administered beta-lactamase will have the same beneficial function of maintaining balance of the gut microbiome and degrading excess antibiotic in patients with GvHD.
Regarding Applicants’ remarks that Fredricks does not teach or suggest a beta-lactamase, the remarks are not persuasive. Fredricks is cited as a 103 reference with at least Bristol et al. and Bristol II, which disclose the therapeutic benefits of beta-lactamases, including P3A, comprising the amino acid sequence having of SEQ ID NO:5 (and having 100% sequence identity to instant SEQ ID NO: 1) for treating C. difficile associated diseases and rebalancing the ecological balance of normal intestinal microbiota by inactivating excreted or unabsorbed antibiotics, thereby maintaining a normal intestinal microbiota (Bristol et al. 0012, 0140; Bristol II at least p. 2, p. 29). Therefore, one of ordinary skill would have a reasonable expectation of success of administering beta-lactamase to maintain a normal intestinal microbiota for treating conditions that result in an undesirable effect of the normal intestinal microbiota caused by antibiotic treatment, where such conditions include Clostridium difficile-associated diseases such as GvHD and/or CDI.
Regarding Applicants’ remarks that Applicants discovered that beta-lactamases of the present claims can be used to reduce the incidence or severity of GvHD and that the results in the specification were unexpected, the remarks are not persuasive. In this instance, the prior art has already recognized beta-lactamases for reducing GvHD in patients also treated with an antibiotic (at least Fredricks) and/or patients undergoing treatment with an antibiotic and having an immune system that is weak (Bristol et al. paragraph 0143), which are the allo-HCT patients of Fredricks/ Callejas-Díaz et al.
For at least these reasons, the 103 rejection is maintained.
No claim is allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/Marsha Tsay/Primary Examiner, Art Unit 1656
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