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 .
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 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.
Priority
The instant application, filed 05/28/2021, is a 371 filing of PCT/EP2019/083992, filed 12/06/2019, and claims foreign priority to application PCTEP2018084057, filed 12/07/2018.
Status of Application, Amendments, and/or Claims
Applicant’s response and amendment of 08/15/2025 is acknowledged. Claims 28 and 44-45 were amended and claims 1-27 are cancelled. Claims 28-47 are currently pending and are examined on the merits herein.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 07/24/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Withdrawn Objections and Rejections
In the office action of 04/15/2025:
Claims 28-47 were rejected under 35 USC 112(b). Applicant’s amendment to independent claim 28 to limit the sequence to which the modifications recited are made has overcome the rejections and the rejections are withdrawn.
Claim 45 was rejected under 35 USC 112(b). Applicant’s amendment to change “of” to “to” has overcome the rejection and the rejection is withdrawn.
Claims 28, 34-44, and 46-47 were rejected under 35 USC 103 over Marthey in view of US’955, US’008, and WO’426; claims 29-33 were rejected under 35 USC 103 over Marthey in view of US’955, US’008, WO’426, and Brahmer; claim 45 was rejected under 35 USC 103 over Marthey in view of US’955, US’008, WO’426, and GenPept. Applicant’s amendment to independent claim 28 to limit the amino acid sequence of the heavy chain of the antibody to SEQ ID NO: 2 has overcome the rejections and the rejections are withdrawn.
The following grounds of rejections are either maintained or new as necessitated by applicant’s amendment to the claims.
Duplicate Claim Warning
Applicant is advised that should claim 44 be found allowable, claim 45 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Claims 44 and 45 have scopes that are the same and are, therefore, duplicates of each other. Instant claim 44 requires that the heavy chain of the antibody in claim 1 include all 434W, 428E, and 311R mutations. Claim 1 requires that the heavy chain of the antibody comprise SEQ ID NO: 2. Making the modifications of claim 44 in SEQ ID NO: 2 results in an antibody Fc domain that is identical to SEQ ID NO: 11, amino acids 236-451, as recited in instant claim 45. Therefore, claim 45 is identical in scope to claim 44.
Claim Rejections - 35 USC § 112(a)- Scope of Enablement- Maintained Rejection
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 28-47 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for alleviating or minimizing symptoms, complications, or similar biochemical indicia of ICP inhibitor-induced diarrhoea, colitis, or enterocolitis, does not reasonably provide enablement for prevention of adverse events of the GI tract, the prevention of progression of ICP inhibitor induced diarrhoea, colitis, and/or enterocolitis to a higher grade toxicity, or the prevention of the development or onset of ICP inhibitor-induced colitis and/or ICP inhibitor-induced enterocolitis. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Enablement is considered in view of the Wands factors (MPEP 2164.01(a)). The court in Wands states: "Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is ‘undue,’ not 'experimentation.'" (Wands, 8 USPQ2d 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. "Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations." (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount or direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. While all of these factors are considered, a sufficient amount for a prima facie case are discussed below.
The nature of the invention
Independent claim 28 recites a method for the treatment of at least one adverse event of the gastrointestinal tract that is induced by a cancer therapy;
Claim 30 recites the administration prevents progression of said ICP inhibitor-induced diarrhoea, colitis, and/or enterocolitis to a higher grade toxicity; and
Claim 31 recites that the pharmaceutical composition is formulated to prevent the development or onset of ICP inhibitor-induced colitis and/or ICP inhibitor-induced enterocolitis in the patient.
The breadth of the claims
The claims are broad in that they encompass prevention of adverse events of the GI tract induced by a cancer therapy and/or prevention of toxicity progression.
The instant specification defines the terms “treat”, “treating”, and “treatment” as to prevent, minimize, or delay the onset of symptoms, complications, or similar biochemical indica (paragraph bridging pages 26-27).
The instant specification defines “prophylactic therapy” as referring to the administration of an active agent as a preventative therapy. The specification further states that the administration of the inventive composition occurs before the onset of symptoms associated with ICP inhibitor induced diarrhoea, colitis, or enterocolitis (page 34, paragraph 4).
In the absence of a limiting definition of “preventing” or “prevent” in the specification, “prevention” is interpreted as defined according to IIME as provided in Wojtczak, A. (2002) Glossary of Medical Education Terms Medical Teacher 24(4): 357; 1-25. IIME defines “prevention” as promoting health, preserving health, and to restore health when it is impaired, and to minimize suffering and distress (page 16, “Prevention”). IIME states that “primary prevention refers to the protection of health by personal and community wide effects, such as preserving good nutritional status, physical fitness, and emotional well-being, immunizing against infectious diseases, and making the environment safe.” IIME states that “secondary prevention can be defined as the measures available to individuals and populations for the early detection and prompt and effective intervention to correct departures from good health”. IIME further states that tertiary prevention consists of the measures available to reduce or eliminate long-term impairments and disabilities, minimize suffering caused by existing departures from good health”.
Thus, in its broadest reasonable interpretation, the prevention of adverse events of the GI tract or the progression or onset of such events, suggests that that the events or progression never occurs and the patient’s health is protected and preserved.
The amount or direction provided by the inventor / the existence of working examples
The examples of the instant disclosure detail the formulation and testing of pharmaceutical compositions comprising the TNFα antibody, Adalimumab, including immediate release pellets and sustained release pellets (Examples 1 and 2; pages 49-51). In example 3 (page 52), the therapeutic efficacy of the antibody following local administration was investigated in an IBD mouse model. The experiment concludes that the topical treatment works in the mouse T cell transfer model as shown by significantly reduced endoscopy score, reduced histological score, reduced cytokines in colon, and less body weight loss (page 54, paragraph 3). Example 4 studied dose response in the treatment of colitis in a colitis mouse model where it was found that local administration of the TNFα inhibitor resulted in reduced inflammation in the colon (page 54). Examples 5 and 6 studied exposure following rectal and intracaecal administration (pages 55-56). Example 7 studied the effect of the composition on nivolumab stimulated human CD4+ T cells and concludes that Ab-REW is possibly a stronger inhibitor of nivolumab-mediated IFNγ secretion then infliximab (page 57). It is noted that Ab-REW is an antibody defined by the amino acid sequences disclosed in the table on page 49.
The examples provided to not demonstrate the prevention of at least one adverse event of the GI tract induced by a cancer therapy in a cancer patient.
Additionally, the disclosure does not discuss, or demonstrate through working examples, a method that could be used to determine that a patient would have predictably developed at least one adverse event of the GI tract such that it could be determined that the event was prevented using the claimed composition.
The state of the prior art / the level of predictability in the art
There are no art recognized methods that could be used to establish that at least one adverse event of the GI tract induced by at least one ICP inhibitor in a cancer patient was prevented using the claimed pharmaceutical composition. Additionally, there are no art recognized methods that could be used to identify subjects that would have necessarily developed such an event in order to determine that the event was prevented.
Shivaji, U.N., et al (2019) Immune checkpoint inhibitor-associated gastrointestinal and hepatic adverse events and their management Ther. Adv. Gastroenterol 12; 1-15, published within a year of the effective filing date of the claimed invention, teaches that ICI-related GI adverse events are common and colitis appears to be the most common side effect, with some studies reporting incidence as high as 30%. The incidence of all-grade colitis was highest in combination therapy with anti-CTLA4/PD-1 and severity was dose dependent. Early intervention is associated with better outcomes (abstract, Results). Shivaji teaches that it has been suggested that intrinsic patient factors may be responsible for IrAEs and this could possibly be identified by identification of genetic epigenic or other predictive markers. For example, female sex, baseline sarcopenia, concurrent medications that have been identified as affecting outcomes and severity of ICI related toxicities. Some bio-markers, such as T cell population, increased eosinophil counts, increased IL-17 levels, reduced circulating IL-6 levels, and gut microbiome have been shown to predict ICI-related AEs. These findings may be useful in predicting IrAEs in the future, but more studies are needed before this is routinely used (page 11, right column, paragraphs 1-2). In another study, gene signatures were studied from patients treated with tremelimumab in a clinical trial to see if there were any predictive markers of ICI-related IrAEs in patients with melanoma. Peripheral blood gene expression signatures were checked pre- and post-treatment for patients who had documented GI toxicities. In the pretreatment data, no gene significantly predicted development of grade 2 or higher colitis, but 16 gene signatures that could possibly distinguish onset of severe diarrhea were identified (paragraph bridging pages 11-12).
The teachings of Shivaji demonstrate that around the time of the effective filing date of the claimed invention, there was no known method that could be used to predictably determine that a patient undergoing ICI therapy would necessarily develop GI related adverse events. Only as high as 30% of patients are reported as having such incidences demonstrating that not all patients develop such toxicities. Additionally, Shivaji teaches numerous factors that have been studied and could play a role in the development of such GI related adverse events.
Martins, F., et al (2019) Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance Clinical Oncology 16; 563-580, also published within a year of the effective filing date, is a review of the various types of irAEs that have emerged to date caused by ICIs (abstract). Martins teaches that the frequency of irAEs is dependent on the agents used, exposure time and the administration dose, but also on the patient’s intrinsic risk factors. Martins further teaches that the timing of appearance is often dictated by the affected organ systems (page 564, key points, first bullet). Martins further teaches that high-risk patients receiving ICIs should be regularly monitored for treatment-related complications by specialized multidisciplinary teams, ideally using personalized surveillance strategy. The application of formal contraindications to the use of ICIs among patients with high risk of irAEs is not supported by well-founded scientific evidence (page 564, key points, bullets 2 and 3). In Table 1, Martins provides a review of the frequency of irAEs with regards to studies and ICI, including ipilimumab, nivolumab, pembrolizumab, ipilimumab plus nivolumab, avelumab, atezolizumab, and durvalumab (page 565). Martins provides the percentage of subjects who had diarrhea or colitis as well as how many had grade 3 or higher events. The data provided by Martins demonstrates that <50% of patients in each of the reported cases developed diarrhea or colitis of any grade. Martins teaches that clinically validated biomarkers enabling individual assessments of the risk of irAEs are still lacking. IrAEs can occur early in the course of treatment and are sometimes associated with a severe clinical presentation. Such variations in severity suggest the presence of pre-existing factors influencing their occurrence. Preventative strategies and pretreatment assessments of target organ function have long been implemented in mitigating specific chemotherapy-related toxicities; however, chemotherapy related toxicities are more predictable than irAEs (page 576, right column, paragraph 1).
Like Shivaji, the teachings of Martins demonstrates that around the effective filing date of the instant invention, there was no known method that could be used to predictably determine whether a specific patient would develop irAEs during ICI therapy. Additionally, Martins demonstrates that less than 50% of patients develop GI related adverse events, demonstrating that not all patients necessarily develop such adverse events. Martins also demonstrates that methods to identify individual risk of irAEs are lacking and that irAEs are not predictable.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure
Based on the disclosure and the prior art, there is no known or disclosed method through which an ordinarily skilled artisan would be able to predictably determine that a subject would have necessarily developed at least one adverse event of the GI tract induced by at least one ICP inhibitor in order to determine that the claimed pharmaceutical composition resulted in the prevention of such events. Therefore, in order to practice the invention as claimed, an ordinarily skilled artisan would have to participate in undue experimentation to determine a method that would allow for the identification of patients who would have developed such toxicities without the claimed composition in order to establish the prevention of the toxicities.
In view of the Wands factors discussed above, a person of ordinary skill in the art would have to engage in undue experimentation to practice the full scope of the claimed invention. As such, the instant claims were determined to not meet the scope of enablement requirement of 35 USC 112(a).
Response to Arguments
Applicant’s arguments filed 08/15/2025 regarding the rejection under 35 USC 112(a) scope of enablement have been fully considered, but were not persuasive.
Applicant argues that the word “prevent” only appears in claims 30 and 31 and only in connection with preventing progression or development or delaying the onset of a specific adverse event already present in the patient. Applicant argues that these are not abstract, prophetic, or speculative events but extant events already being experienced by the patient being treated.
Contrary to applicant’s arguments, the claims that recite or encompass prevention do not do so only in patients who are already experiencing the claimed adverse events. For instance, claim 28 recites treatment which is defined in the specification as encompassing prevention of the onset of symptoms, complications, or similar biochemical indica (paragraph bridging pages 26-27). As the treatment is encompassing prevention of the “onset” of the symptoms, complications, or similar biochemical indica, the claim includes patients for whom “onset” has not occurred. Similarly, claim 31 recites that the development or onset of toxicities is prevented, also indicating that the patient does not already have the recited toxicities. Claim 30, which recites that the claimed method prevents progression of the toxicities to a higher grade, is the only one of the three claims discussed that limits the patient to already having some degree of diarrhoea, colitis, and/or enterocolitis, and claims prevention of these from progressing to a higher grade.
As discussed in the rejection, there was, and is, no art recognized method to determine that a patient would have predictably developed the claimed adverse events, or that progression would have predictably occurred, making the determination that the adverse event or progression was prevented unpredictable. Because of this, one of ordinary skill in the art would not be able to predictably identify that the onset or progression would have happened without the treatment such as to identify that it was prevented. As one of ordinary skill in the art would not be able to practice the invention as claimed, specifically the prevention of the adverse events or progression thereof, the claims do not meet the scope of enablement requirement of 35 USC 112(a).
With regards to the definition of “treatment” in the specification, applicant argues that the intrinsic record makes it clear that the focus is on the remedy and rehabilitation of specific GI events known to accompany and be induced by ICP inhibitor therapy. Applicant further argues that the suggestion that prophylactic therapy falls outside of the bounds of ordinary skill and routine experimentation is rebutted by the reference US’955 which characterizes administration of an antibody composition as a prophylactic treatment.
The scope of enablement rejection pertains to the ability of one of ordinary skill in the art to predictably use the claimed invention and, in order to do so, one of ordinary skill in the art would need to predictably identify that the adverse events were prevented using the claimed method. As there is no known method to predictably identify that the adverse events would have occurred without the claimed treatment, there is no way to predictably identify that the treatment resulted in prevention of the adverse events. As discussed in detail in the rejection under 112(a), the art demonstrates that not all patients receiving ICI develop GI related adverse events. For instance, Shivaji teaches that only as high as 30% of patients have such incidences and also demonstrates that numerous factors could contribute to the development of such events. Similarly, Martins teaches that less than 50% of patients develop GI related adverse events and teaches that there are no clinically validated biomarkers enabling individual assessment of the risk of irAEs.
While applicant argues that US’955 suggests prophylactic treatment, this alone does not suggest that a method exists in the art that would allow for the predictable determination that the claimed method resulted in prevention. Furthermore, US’955 does not provide a method to predictably identify which patients receiving ICP inhibitor therapy would develop such adverse events in order to establish that the adverse events were prevented. It is also noted that inhibition or the intention of prevention is different from the act of prevention as the latter requires a determination that an individual would have had onset of the adverse events without treatment.
The invention, however, is enabled for alleviating or minimizing symptoms, complications, or similar biochemical indicia of ICP inhibitor-induced diarrhoea, colitis, or enterocolitis. In order to overcome the rejection it is suggested that limitations encompassing prevention be replaced with language such as alleviating and/or minimizing at least one adverse event.
Claim Rejections - 35 USC § 112(a)- Written Description
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 28-47 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 28, as amended, claims that the heavy chain of the TNFα antibody, or functional fragment thereof, comprises SEQ ID NO: 2 with the recited modifications. The claim further encompasses the use of the TNFα antibody, or functional fragment thereof, in the treatment of at least one adverse events of the GI tract induced by one or more ICP inhibitors.
Instantly claimed SEQ ID NO: 2 is the full heavy chain of an antibody and includes a heavy chain variable region comprising 3 heavy chain CDRs. Therefore, the claim is drawn to a genus of TNFα antibodies in which the antibody is limited by only the heavy chain and includes the combination of this heavy chain with any light chain/light chain variable region/light chain CDRs.
The instant disclosure, however, does not describe a representative number of species of the claimed genus performing the claimed functions, nor does the disclosure identify a structure-function relationship that could be used to predictably identify which light chain CDRs could be used in combination with the claimed heavy chain in order to arrive at an antibody or antigen-binding fragment thereof with the claimed functions. This is particularly the case as the claims only recite 3 heavy chain CDRs and do not require a full complement of 6 CDRs, specifically 3 from the heavy chain variable region and 3 from the light chain variable region, which are the art recognized binding sites of antibodies.
The examples of the instant disclosure studied formulations of the TNFα antibodies Adalimumab, and release of the antibody from delayed (enteric) release pellet cores. The examples further studied therapeutic efficacy of the TNFα antibodies Ab-REW and infliximab. Each of these antibodies comprise specific heavy and light chain CDR combinations which result in binding and inhibition of TNFα.
The disclosure does not provide a representative number of species of the claimed antibody in which any light chain CDRs are used in combination with the heavy chain CDRs of the heavy chain region claimed resulting in the functions of being a TNFα antibody and treating at least one adverse event of the GI tract caused by ICP inhibitor(s). The disclosure also does not provide a structure-function correlation that would allow for the identification of which light chains CDRs could be used in combination with the heavy chain CDRs of the claimed sequence to result in the claimed functions.
The state of the art around the effective filing date of the claimed invention also does not provide a representative number of species or a predictable structure-function relationship to support the full scope of the claimed genus.
For example, Chiu, M.L., et al (2019) Antibody structure and function: The basis for engineering therapeutics Antibodies 8(55); 1-80 teaches that, the antigen-binding site of immunoglobulins is formed by the pairing of the variable domains (VH and VL) of the Fab region. Chiu teaches that each domain contributes three complementarity determining regions (CDRs), specifically, three from the VL and three from the VH, and that the six CDR loops are in proximity to each other resulting from the orientation of the VL and VH regions. Chiu teaches that the configuration of the VL and VH brings the three CDRs of the VL and VH domains together to form the antigen-binding site (page 4, paragraph 2). These teachings of Chiu demonstrate that the interaction between the heavy and light chain variable domains effect the conformation of the binding region of the antibody and therefore the antibody’s ability to bind to its target. Furthermore, the teachings of Chiu point out that the binding site is formed by the combination of the heavy and light chain CDRs (six regions) together.
Chailyan, A., et al (2011) The association of heavy and light chain variable domains in antibodies: implications for antigen specificity FEBS Journal 278; 2858-2866 teaches that the antigen-binding site of immunoglobulins is formed by six regions, three from the heavy chain variable domains, and three from the light chain variable domains which, on association of the two chains, form the conventional antigen binding site of the antibody (abstract). Chailyan teaches that the mode of interaction between the heavy and light chain variable domains impacts the relative position of the binding loops and has an effect on the overall conformation of the binding site (abstract).
Rabia, L., et al (2018) Understanding and overcoming trade-offs between antibody affinity, specificity, stability, and solubility Biochem Eng. J. 15(137); 365-374 discusses similar challenges faced during antibody optimization. Rabia discusses the challenges with optimizing antibody properties and states that “natural antibody affinity maturation relies on the introduction of somatic mutations followed by clonal selection of antibody variants with improved affinity. However, not all somatic mutations contribute to antibody affinity… antibodies accumulate some somatic mutations to increase affinity and others to compensate for the destabilizing effects of affinity-enhancing mutations” (page 2, paragraph 4). Rabia further provides an example of researchers who introduced mutations throughout variable frameworks and CDRs and created libraries to sort antibody variants with high antigen binding. In this case an antibody was identified that displayed increased affinity but had a significant reduction in stability (page 3, paragraph 2). Rabia concludes by stating that “a final key area of future work is the development of improved computational methods for predicting mutations in antibody CDRs and frameworks that co-optimize multiple antibody properties” and that “future efforts will also need to improve structural predictions of antibody CDRs – especially the long and highly variable heavy chain CDR3 – to accurately predict CDR mutations that are beneficial to different antibody properties” (page 9, paragraph 4 – page 10 paragraph 2).
Chiu and Chailyan demonstrate that antibody function was known to be a result of a full complement of six CDRs, three from the heavy chain and three from the light chain, which form the antigen binding site of the antibody. The teachings of Rabia demonstrate that CDR structure was not predictable and that even changing amino acids in known CDRs could result in a non-functional antibody. Based on these teachings, an ordinarily skilled artisan would not have been able to predictably identify which species of the instantly claimed genus would be capable of performing the claimed function. This is particularly the case in the absence of a full complement of heavy and light chain CDRs.
It is not evident from the disclosure, or the prior art, that applicant was in possession of a representative number of species supporting the entire genus of antibodies that are encompassed by the instant the claims. Additionally, there is no disclosed or art recognized structure-function relationship between antibody structure and functionality which would allow for the predictable pairing of light chain CDRs with the heavy chain CDRs of the claimed heavy chain while retaining function. Therefore, the instant claims were found to not meet the written description requirement.
It is noted that there would be support if either the entire complement of 6 CDRs were claimed or if the claimed sequence limited only the heavy chain Fc region.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 28 and 34-47 are rejected under 35 U.S.C. 103 as being unpatentable over Marthey, L., et al (2016) Cancer immunotherapy with anti-CTLA4 monoclonal antibodies induces an inflammatory bowel disease Journal of Chron’s and colitis 10(4); 395-401 in view of US 9,079,955 B2 (Fox, B.S.) Jul. 14, 2015, US 8,389,008 B2 (Baichwal, A.R., et al) Mar 5, 2013, EP 3 219 726 A1 (Gunde, T., et al) 20 Sept 2017, GenPept PRF: 1605217A; human immunoglobulin gamma 1 chain constant region, 21-OCT-1996, and WO 2017/158426 A1 (Foss, S., et al) 21 September 2017.
Marthey teaches that gastroenterologists are increasingly faced with anti-CTLA-4 induced enterocolitis, particularly in the most severe forms. There is a need for more information, such as inflammation site and endoscopic features, as well as outcomes with medical and surgical treatment. Marthey provides a detailed description of anti-CTLA-4-induced enterocolitis in a relatively large series of patients referred to inflammatory bowel disease specialists. The findings suggest that anti-CTLA-4 induced enterocolitis is a particular form of IBD with similarities to both Chron’s disease and ulcerative colitis (paragraph bridging left and right columns, page 396). Marthey recorded anti-CTLA-4 enterocolitis cases observed in patients that had endoscopic signs of inflammation after having received anti-CTLA-4 infusion (page 396, right column, paragraph 3). Marthey teaches that the anti-CTLA-4 antibodies studied were ipilimumab and tremelimumab and that the antibodies were administered by intravenous infusion (page 396, right column, paragraph 3) which is a form of systemic administration. The study included 39 patients with anti-CTLA-4 enterocolitis (page 397, left column, paragraph 2) all of whom had endoscopic inflammation of the colon (page 397, right column, paragraph 3) with the most frequent symptom being diarrhea (abstract, results). Marthey further discloses that 36 patients received anti-CTLA-4 without interruption and the median time between first infusion of anti-CTLA-4 and symptoms was 34 days with a range from 3-91 days (page 397, right column, paragraph 1). Marthey further teaches that patients were receiving anti-CTLA-4 therapy every 3 or 4 weeks (page 396, right column, paragraph 3), suggesting that the patients were actively undergoing the anti-CTLA-4 therapy. Marthey discusses the site of the inflammation in the patients on Table 2, and teaches inflammation in both the ileum and features of the large intestine, such as the ascending colon, transverse, descending colon, sigmoid colon, and rectum (Table 2, page 398). Marthey teaches that twelve of the patients received infliximab (page 398, right column, paragraph 1). Marthey teaches that 37% of patients were successfully treated with steroids and, by comparison, 10 out of 12 (83%) responded to infliximab after they had failed to improve with steroids. Therefore, due to its severe course, patients with anti-CTLA-4 induced enterocolitis should be carefully monitored and a rapid escalation to infliximab should be advocated in patients who do not respond to steroids (page 400, left column, paragraph 2). Marthey also states that treatment with adalimumab induced and maintained remission in one of the studied patients (page 399, left column, paragraph 1).
Marthey, however, does not teach that the anti-TNFα antibodies are in a pharmaceutical composition that is formulated for topical administration to an affected part of the GI tract of the patient, including the ileum and/or the large intestine, or that the heavy chain of the antibody comprises SEQ ID NO: 2 with modifications including 434W, and optionally 428E and/or 311R according to EU numbering.
US’955 relates to the application of antibodies and stabilized antibodies to the gastrointestinal tract of a patient and describes the use of topical antibody therapeutics for use in patients (column 4, lines 59-57). US’955 teaches that the antibodies are anti-TNF antibodies, specifically TNF-α antibodies, and that the antibody can be a monoclonal antibody, a humanized antibody, a chimerized antibody, or an antibody fragment or synthetic molecule designed to mimic the function of an antibody (column 13, line 65-column 14, line 4; column 4, lines 33-34).
US’955 further teaches that the antibodies are IgG1 antibodies (column 35, claim 7) indicating that the antibodies comprise an IgG1 Fc region.
US’955 teaches that the antibody is in a pharmaceutical composition comprising a therapeutically effective amount of the antibody formulated together with one or more pharmaceutically acceptable carriers or excipients (column 24, lines 31-40). US’955 teaches the topical administration of the antibody and that topical administration to the GI tract is defined as local and/or surface administration to the oral cavity, delivery by oral or rectal administration to the GI tract, or administration by any other route that brings the antibody in contact with the luminal aspect of the GI tract (column 4, lines 25-29; column 10, lines 65-66). US’955 teaches an embodiment in which the composition is formulated as a solid dosage form for oral administration (column 35, claim 2). US’955 further teaches that solid dosage forms for oral administration include capsules, tablets, pills, and granules (column 25, lines 20-21). US’955 further teaches that the solid dosage forms can be prepared with coatings and shells well known in the pharmaceutical formulation art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal track, optionally in a delayed manner (column 25, lines 57-65). US’955 teaches that compositions for rectal administration are preferably suppositories or in the form of an enema (column 25, lines 11-18).
US’955 further teaches that it is advantageous to be able to apply antibody therapeutics to diseases of the digestive tract. Most antibody therapies in current use are designed to be delivered systemically and are administered to patients by injection. Injected antibodies have been shown to be useful in the treatment of inflammatory bowel disease, and may also be useful in the treatment of other diseases of the digestive tract. However, administration of the antibodies systemically may affect physiological processes throughout the body, rather than just within the digestive tract, and this may be disadvantageous for some diseases. For instance, anti-TNF antibodies used for the treatment of inflammatory bowel disease are associated with serious side effects. Therefore, it would be useful to be able to apply the antibody therapeutics directly to the digestive tract (column 2, lines 27-41).
US’955 also teaches administration of the antibody composition as a prophylactic treatment (column 24, lines 8-30).
US’955 further teaches the use of the composition in the treatment of mucositis, which is a serious and painful condition that results from radiation therapy and/or chemotherapy for cancer treatment. According to a report by the National Comprehensive Cancer Network, mucositis is the most significant adverse symptom of cancer therapy reported by patients. Damage can occur throughout the digestive tract and frequently results in cessation or dose reduction of the cancer therapy. US’955 also teaches types of mucositis including intestinal mucositis which presents with nausea, vomiting, abdominal pain and diarrhea and most commonly affects the small intestine, but is also seen in the stomach and large intestine (column 1, lines 40-51 and lines 57-61). US’955 teaches that for the treatment of mucositis, the anti-TNFα antibody is administered topically to the oral cavity or topically to the GI tract and that the antibody can be administered prior to the initiation, concurrently with, and or following a cycle of the chemotherapy and/or radiation therapy (column 13, lines 33-65). US’955 further provides examples in which GI mucositis in mice was induced followed by oral administration of a TNFα immunoglobulin (columns 26-29). Mice received anti-TNF antibody or control anti-influenza antibody then evaluated daily through day 7 for the presence of diarrhea. Dosing with anti-TNF antibody, but not anti-influenza antibody, was found to reduce the incidence of severe delayed onset diarrhea (column 28, Example 3).
US’008 teaches that specific delivery of drugs and pharmaceutical compositions to the colon is important in the treatment of a wide variety of diseases and conditions, for example, Chron’s disease, colitis, irritable bowel syndrome and the like (col. 1, lines 19-23). Targeting of drugs to the colon provides the ability to locally treat large bowel diseases, thus avoiding or decreasing systemic effects of drugs or inconvenient and painful transcolonic administration of the drugs (col. 1, lines 33-36). US’008 teaches an oral controlled release delivery system that is adaptable to delay the release of a drug such that the drug is delivered to the colon of a human (col. 2, lines 3-6) and is capable of passing over the entire tract of the small intestine so that the active ingredients can be released directly in the colon (col. 1, lines 46-51). US’008 teaches that drugs for use in the invention include polypeptides, proteins, and derivatives thereof (col. 24, lines 15-17) including anti-tumor necrosis factor substances, such as infliximab (col. 23, lines 55-56).
US’008 teaches that the dosage form is a solid oral dosage form, such as a tablet (col. 19, lines 19-22) and comprises an inner core containing the active ingredient that is compression coated with a coating that provides a delayed release of the drug from the dosage form after the dosage form is orally administered to a human (col. 2, lines 19-24).
US’008 further teaches that the compression coating comprises a natural or synthetic gum which can function as a gelling agent, causing the core to be surrounded by the gel when the coated tablet is in an environmental fluid and, thereby, causing the drug to be released after diffusion of the environmental fluid through the compression coating, the dissolution of the drug into the environmental fluid, and the egress of the dissolved drug into the fluid surrounding the compression coated tablet. US’008 teaches that gums for use in the compression coating include: pectin, guar gum, chitosan, alginates, locust bean gum, carrageenan, and/or scleroglucan (col. 13, lines 38-43, 51, and 66). US’008 further teaches that the compression coating comprises a heteropolysccharide such as Xanthan gum (col. 14, lines 1-3) as well as pharmaceutically acceptable excipients such as a starch (col. 14, lines 63-67).
US’008 further teaches that the core comprising the active agent can be formulated as a sustained release core for the sustained release of the active agent. When the core comprising the active agent is formulated for sustained release, the core can be prepared in a number of ways known in the art. For example, the active agent can be incorporated in a sustained release matrix and thereafter compressed into a core, or a sustained release material can be coated onto the immediate release core to provide for the sustained release of the active agent. Alternatively, a combination of the compressed sustained release matrix and sustained release coating on the core can be used (col. 9, lines 29-40). US’008 teaches that sustained release means that once the drug is released from the formulation, it is released at a controlled rate such that the therapeutically beneficial blood levels of the medicament are maintained over an extended period of time from the start of the drug release, for example, providing a release over a time period from about 4 to about 24 hours (col. 7, lines 3-10), suggesting a time-dependent release.
US’008 further teaches that the sustained release materials can include methacrylic acid polymers and copolymers (col. 10, lines 40-43). US’008 teaches that in certain embodiments the core may be formulated to provide for the sustained release of the active agent through the use of an immediate release core with a sufficient amount of a hydrophobic coating to provide for the sustained release of the active agent from the immediate release core. For example, the hydrophobic coatings include alkylcelluloses, such as ethylcellulose, copolymers of acrylic and methacrylic acid esters, and the like (col. 10, line 62-col. 11, lines 1-8).
US’008 teaches that the composition can comprise a sustained release core, or a combination of the sustained release core and a sustained release coating (col. 9, lines 29-40). US’008 also teaches the use of a delayed release coating, specifically a compression coating, on the core (col. 2, lines 19-24). When the core of the disclosure is formulated as a sustained release core, an ordinarily skilled artisan would reasonably recognize that the core would be coated with the compression coating as US’008 is teaching that the formulations comprise a core with the active agent and a delayed release compression coating (col. 1, line 64 – col. 2, lines 1-6). US’008 further teaches that the delayed release of the drug may further be varied by utilizing a further coating between the core and the compression coating (col. 17, lines 36-38). Based on this teaching, and ordinarily skilled artisan would reasonably envision a composition comprising a core, a sustained release coating, and the compression coating.
Ep’726 teaches antibody molecules and functional fragments thereof, capable of binding to TNFα (page 2, [0001]). EP’726 teaches that TNFα is a homo-trimeric pro-inflammatory cytokine that is released by and interacts with cells of the immune system. TNFα has also been shown to be up-regulated in a number of human diseases, including chronic diseases such as rheumatoid arthritis, Chron’s disease, ulcerative colitis, and multiple sclerosis (page 2, [0002]).
EP’726 teaches an anti-TNFα antibody, 16-22-H05, comprising a light chain of SEQ ID NO: 52 and a heavy chain of SEQ ID NO: 53 (page 19 Table 1; pages 9-10, [0043]) . EP’726, SEQ ID NO: 53 has the following alignment with instant SEQ ID NO: 2:
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SEQ ID NO: 53 of EP’726 differs from instant SEQ ID NO: 2 in two mismatches (identified in the alignment above with arrows) that are in the Fc region of the heavy chain.
EP’726 further teaches that the antibody is an IgG, preferably a subclass 1, i.e., an IgG1, molecule (pages 9-10, [0043]).
GenPept discloses the amino acid sequence of the human immunoglobulin gamma 1 (IgG1) heavy chain constant region. The IgG1 heavy chain constant region of GenPept comprises amino acid sequences that match the Fc region of the heavy chain of SEQ ID NO: 2, as shown in the ABSS alignment below:
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WO’426 teaches compositions and methods for antibody-mediated therapy, particularly engineered immunoglobulins with altered half-life (abstract). WO’426 teaches mutant immunoglobulins comprising at least one or more mutations, preferably in the Fc region or hinge of the immunoglobulin and that such mutations can alter the function of the immunoglobulin in a desired way. For example, the use of a variant immunoglobulin comprising at least one mutation in the Fc region can modulate FcRN binding to increase the in vivo half-life of the antibody, which is advantageous for therapeutic antibodies (page 15, lines 20-26).
WO’426 teaches mutations in the Fc regions of IgG1, IgG2, IgG3, or IgG4 including in positions selected from 311, 434, 428, 438, or 435. WO’426 teaches specific mutations consisting of N434W or, alternatively, Q311R/N434W/M428E (page 3, lines 30-31). WO’426 further teaches that the numbering of the amino acid residues in the Fc region are according to the Eu numbering system, also called the EU index (page 6, lines 2-5) and provides sequence comparisons where these modifications were made in a wild type IgG1 Fc region (Figure 3, Figure page 3/9, pdf page 57). WO’426 further states that, as used in the disclosure, “Fc region” is used to define a C-terminal region of an immunoglobulin heavy chain that contains at least a portion of the constant region (page 5, lines 31-33).
WO’426 teaches that cytokines and soluble targets, such as TNF superfamily members, are preferred targets for use with t