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 .
Election/Restrictions
Applicant’s election without traverse of Species of (Ia) non-glycosylated GM-CSF (Ib) alanine substituted at S22, S24, T27, S26, N44, and N54A (II) Crohn’s disease and (III) an anti-inflammatory agent in the reply filed on 12/5/25 is acknowledged.
Claim Status
Claims 1-69 are cancelled. Claims 70-89 are pending.
Claims 71 and 83 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12/5/25.
Claims 70, 72-82, and 84-89 are currently under consideration for patentability under 37 CFR 1.104.
Information Disclosure Statement
The information disclosure statements filed on 11/1/22 have been considered. Signed copies are enclosed.
The references lined through were not considered because the references were not properly cited including date and author (NPL 11) (see 37 CFR 1.98(b)) or a copy of the reference was not provided (Foreign reference 3) (see 37 CFR 1.98(a)).
Notably, the disclosure statement filed lists a Search Report. The listing of the references cited in a Search Report itself is not considered to be an information disclosure statement (IDS) complying with 37 CFR 1.98. 37 CFR 1.98(a)(2) requires a legible copy of: (1) each foreign patent; (2) each publication or that portion which caused it to be listed; (3) for each cited pending U.S. application, the application specification including claims, and any drawing of the application, or that portion of the application which caused it to be listed including any claims directed to that portion, unless the cited pending U.S. application is stored in the Image File Wrapper (IFW) system; and (4) all other information, or that portion which caused it to be listed. In addition, each IDS must include a list of all patents, publications, applications, or other information submitted for consideration by the Office (see 37 CFR 1.98(a)(1) and (b)), and MPEP § 609.04(a), subsection I. states, "the list ... must be submitted on a separate paper." Therefore, the references cited in the Search Report have not been considered. Applicant is advised that the date of submission of any item of information or any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the IDS, including all "statement" requirements of 37 CFR 1.97(e). See MPEP § 609.05(a).
Note: If copies of the individual references cited on the Search Report are also cited separately on the IDS (and these references have not been lined-through) they have been considered.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Written Description
Claims 70, 72-82, and 84-89 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.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.”
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the Applicants were in possession of the claimed genus.
The instant claims are directed to a method of preventing or treating one or both of an inflammatory bowel disease (IBD) and a condition resulting from IBD in a subject comprising selecting the subject having or at risk of having the IBD and administering a GM-CSF protein to the subject under conditions effective to prevent or treat one or both conditions. The GMCSF can be glycosylated or non-glycosylated, and can be administered in a number of routes. The subject can be selected based on the presence of anti-GMCSF autoantibodies in a sample from the subject, and an additional therapeutic can be administered.
There are multiple issues with regard to written description for the claimed method.
First, the GM-CSF polypeptide composition is not properly described. The specification indicates that the term “GM-CSF protein” encompasses any number of alterations of any locations in the protein, without limit. For example, paragraph [0050] states that “once nucleic acid sequence and/or amino acid sequence information is available for a native protein (e.g. a native GM-CSF protein), a variety of techniques become available for producing virtually any mutation in the native sequences.” Paragraph [0051] states that “Mutants of a naturally occurring GM-CSF may be desirable in a variety of circumstances.” Paragraph [0052] states that “The present disclosure, in one embodiment, may relate to polypeptides with conservative amino acid substitutions, insertions, and/or deletions with respect to the mature native GM-CSF sequence.” Therefore, the specification encompasses any GM-CSF with any number of mutations, additions, or deletions, in any location in the protein. One example of a precursor GM-CSF protein found in the art (see Guyon et al (WO 2009/152944 A1; filed 5/29/09; published 12/23/09; as discussed below) has approximately 144 amino acids, and the mature protein has approximately 127 amino acids. Mutation of any two amino acids within these proteins can produce over 36,000 proteins. This level of variation is only for two mutations. If 5 mutations are selected, over 400 million proteins can be created. The description of a very limited number of single point mutations does not adequately describe the vast breadth of the encompassed genus. The proteins must possess specific functions, including preventing or treating inflammatory bowel diseases and all possible conditions that result from the IBD, without defining said conditions. Applicant has not sufficiently described a structure for the GMCSF proteins that correlates with these functions.
Second, the possible subjects encompassed by the method are not described. Applicant has only defined the encompassed subjects as “having or at risk of having the IBD,” without defining any criteria that would indicate that a subject was “at risk”. Without criteria for identifying such subject, it is impossible to adequately describe the claimed method.
Third, the “conditions effective to prevent or treat one or both of the IBD and a condition resulting from the IBD” are not adequately described. Applicant has not adequately described what criteria are required for a condition to be considered “resulting from the IBD”. Therefore it is impossible to identify the subjects encompassed by the claimed method.
The claimed proteins, conditions, and subjects have no correlation between the structure and function of the method. The specification provides no guidance regarding which criteria must be met for each to be capable of the required functions. Further, a representative number of species for the encompassed method has not been adequately described. Therefore, the specification provides insufficient written description to support the genus encompassed by the claim. Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that
"applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
The skilled artisan cannot envision the detailed chemical structure of the encompassed polypeptides, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. The nucleic acid and/or protein itself is required. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. In Fiddes v. Baird, 30 USPQ2d 1481, 1483, claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404. 1405 held that:
...To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines Inc. , 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli , 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (" [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2datl966.
Protein chemistry is one of the most unpredictable areas of biotechnology. This unpredictability prevents prediction of the effects that a given number or location of mutation will have on a protein (such as TNF or a cytokine) As taught by Skolnick et al (Trends Biotechnol. 2000 Jan;18(1):34-9), sequence based methods for predicting protein function are inadequate because of the multifunctional nature of proteins (see e.g. abstract). Further, just knowing the structure of the protein is also insufficient for prediction of functional sites (see e.g. abstract). Sequence to function methods cannot specifically identify complexities for proteins, such as gain and loss of function during evolution, or multiple functions possible within a cells (see e.g. page 34, right column). Skolnick advocates determining the structure of the protein, then identifying the functionally important residues since using the chemical structure to identify functional sites is more in line with how a protein actually works (see e.g. page 34, right column).
The sensitivity of proteins to alterations of even a single amino acid in a sequence are exemplified by Burgess et al. (J. Cell Biol. 111:2129-2138, 1990) who teach that replacement of a single lysine reside at position 118 of acidic fibroblast growth factor by glutamic acid led to the substantial loss of heparin binding, receptor binding and biological activity of the protein and by Lazar et al. (Mol. Cell. Biol., 8:1247-1252, 1988) who teach that in transforming growth factor alpha, replacement of aspartic acid at position 47 with alanine or asparagine did not affect biological activity while replacement with serine or glutamic acid sharply reduced the biological activity of the mitogen. These references demonstrate that even a single amino acid substitution will often dramatically affect the biological activity and characteristics of a protein.
Further, Miosge (Proc Natl Acad Sci U S A. 2015 Sep 15;112(37):E5189-98) teach that Short of mutational studies of all possible amino acid substitutions for a protein, coupled with comprehensive
functional assays, the sheer number and diversity of missense mutations that are possible for proteins means that their functional importance must presently be addressed primarily by computational inference (see e.g. page E5189, left column). However, in a study examining some of these methods, Miosge shows that there is potential for incorrect calling of mutations (see e.g. page E5196, left column, top paragraph). The authors conclude that the discordance between predicted and actual effect of missense mutations creates the potential for many false conclusions in clinical settings where sequencing is performed to detect disease-causing mutations (see e.g. page E5195, right column, last paragraph). The findings in their study show underscore the importance of interpreting variation by direct experimental measurement of the consequences of a candidate mutation, using as sensitive and specific an assay as possible (see e.g. page E5197, left column, top paragraph). Additionally, Bork (Genome Research, 2000,10:398-400) clearly teaches the pitfalls associated with comparative sequence analysis for predicting protein function because of the known error margins for high-throughput computational methods. Bork specifically teaches that computational sequence analysis is far from perfect, despite the fact that sequencing itself is highly automated and accurate (p. 398, column 1). One of the reasons for the inaccuracy is that the quality of data in public sequence databases is still insufficient. This is particularly true for data on protein function. Protein function is context dependent, and both molecular and cellular aspects have to be considered (p. 398, column 2). Conclusions from the comparison analysis are often stretched with regard to protein products (p. 398, column 3). Further, although gene annotation via sequence database searches is already a routine job, even here the error rate is considerable (p. 399, column 2). Most features predicted with an accuracy of greater than 70% are of structural nature and, at best, only indirectly imply a certain functionality (see legend for table 1, page 399). As more sequences are added and as errors accumulate and propagate it becomes more difficult to infer correct function from the many possibilities revealed by database search (p. 399, paragraph bridging columns 2 and 3). The reference finally cautions that although the current methods seem to capture important features and explain general trends, 30% of those features are missing or predicted wrongly. This has to be kept in mind when processing the results further (p. 400, paragraph bridging cols 1 and 2).
One key issue is the prediction of protein function based on sequence similarity, which could be one way to identify the functional protein variants that are useful in the instant claims. Kulmanov et al (Bioinformatics, 34(4), 2018, 660–668), teach that there are key challenges for protein function prediction methods (see e.g. page 661, left column). These challenges arise from the difficulty identifying and accounting for the complex relationship between protein sequence structure and function (see e.g. page 661, left column). Despite significant progress in the past years in protein structure prediction, it still requires large efforts to predict protein structure with sufficient quality to be useful in function prediction (see e.g. page 661, left column). Another challenge is that proteins do not function in isolation. In particular higher level physiological functions that go beyond simple molecular interactions will require other proteins and cannot usually be predicted by considering a single protein in isolation (see e.g. page 661, left column). Due to these challenges it is not obvious what kinds of features should be used to predict the functions of a protein and whether they can be generated efficiently for a large number of proteins, such as the vast genus of GMCSF proteins encompassed by the instant claims (see e.g. page 661, left column).
Given the teachings of these references that point out the limitations and pitfalls of using sequence to predict functions, and the lack of a representative number of species across the breadth of the genus, one of skill in the art would reasonably conclude that the full breadth of the claims was not adequately described and therefore wouldn’t meet the written description provision of 35 USC 112(a).
Predicting whether or not an agent will be able to treat a particular disease is fraught with obstacles, even if the patient population has a well-understood disease. As taught by Ma (Modern Drug Discovery 2004, 7(6)), any results from in vitro screening often poorly correlate with in vivo results because the complicated physiological environment is absent in the in vitro system (see page 30, left column).
In addition, predicting the success of a treatment for inflammatory disease presents challenges beyond initial screening. For example, regarding autoimmune disease, according to Steinman et al (Nat Med. 2012 Jan 6;18(1):59-65), there are no approved clinical tests that are effective at predicting the therapeutic success or toxicity of treatments for autoimmune diseases (see page 59). Further Steinman et al teach that a single therapeutic strategy is probably not suitable for all autoimmune diseases or even for individual subsets of patients within one diagnostic category, as there may be heterogeneous biology underlying some of these clinical entities (see page 61). Steinman et al give the example of biologics targeting TNF and its receptors, which are effective in rheumatoid arthritis, Crohn's disease and psoriasis, but which cause marked worsening of disease in multiple sclerosis (see page 60). Blumberg et al (Nat Med.; 18(1): 35–41) teach that one of the greatest problems in translating therapies into clinical practice in autoimmunity are the numerous failures that have been the results of clinical trials. Despite the rapid progress that has been made in understanding the immune system, most of the underlying data has come from animal models, which necessarily only partially represent what is observed in humans. To compound this limitation, there exists no standardized definition of the normal human immune system, no comprehensive understanding of how this normal system is altered in autoimmune diseases and no understanding of the relationship between these immunophenotypic characteristics and either the genetic composition of the host or the environmental stimuli that either promote or protect from the development of autoimmunity (see pages 1-3).
For inflammatory bowel disease in particular, Hafez (World J Methodol 2025 December 20; 15(4): 107643) teaches that IBD is primarily comprised of CD and UC (see e.g. Hafez page 2). These conditions are characterized by persistent inflammation of the gastrointestinal tract, significantly affecting patients’ daily lives (see e.g. Hafez page 2). Despite recent developments in treatment options, including small molecules targeting various inflammatory pathways, many patients still experience treatment failures or reduced responses over time (see e.g. Hafez page 3). Therapies for IBD face significant challenges for their effectiveness (see e.g. Hafez page 3). While biologics and small-molecule treatments have revolutionized IBD control, many patients do not benefit from initial treatment (see e.g. Hafez page 3). Furthermore, secondary loss of response is common, as almost half of the patients who initially respond to biologics eventually experience treatment failure over time, complicating long-term management (see e.g. Hafez page 3). The effectiveness of biologics can vary widely among different patient groups depending on many factors, such as the type of disease, whether it is CD or UC (see e.g. Hafez page 4). Additionally, effectiveness and safety may be influenced by a patient’s genetics, medical and family history, compliance, and response to treatment (see e.g. Hafez page 4). The teachings of Hafez therefore demonstrates the unpredictability in selecting patients for treatment, and in achieving successful therapeutic benefit.
Appiah et al (J. Clin. Med. 2025, 14, 6119) teaches that the treatment of IBD has traditionally involved corticosteroids, immunosuppressants, and 5-aminosalicylates (see e.g. Appiah page 2). Biologic therapies have significantly changed the landscape of treatment for moderate-to-severe disease, particularly in patients who are refractory to conventional therapies (see e.g. Appiah page 2). However, these treatments are associated with many limitations, including high costs, side effects, and loss of efficacy over time (see e.g. Appiah page 2). Importantly, even with established therapy, primary non-response rates remain at 30–40% (see e.g. Appiah page 2). Despite advances in IBD research, important challenges persist in therapy, including with biological molecules (see e.g. Appiah page 6). These include substantial variability in patient response patterns, with individual patients demonstrating different response kinetics and durability even within the same therapeutic class (see e.g. Appiah page 6). The risk of immunogenicity remains a concern across all biologic agents, potentially leading to loss of efficacy and requiring ongoing monitoring and management strategies (see e.g. Appiah page 6).
This unpredictability is further exacerbated by lack of understanding of the causative factors for IBD, which impacts the ability of medical providers to prevent IBD or related conditions. For example, Ho et al (Inflamm Bowel Dis, Volume 25, Number S2, June 2019) teaches that the causative factors for IBD are not fully understood (see e.g. Ho, page S13). Two fundamental questions about Crohn’s disease (CD)
and ulcerative colitis (UC) that have yet to be answered are what causes the disease and, once the disease is in remission with medical or surgical therapy, what causes the disease to relapse (see e.g. Ho, page S14). The importance of genetic susceptibility has been established in the last decade and genetic risk variants have been identified, but the lack of complete gene penetrance and the rapid rise of IBD incidence in certain geographic regions suggest that the interaction between genetic and environmental factors contributes to IBD (see e.g. Ho, page S13). Without understanding the causative nature of IBD, the identification of preventative therapies is highly unpredictable.
Adequate written description requires more than a mere statement that is part of the invention. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. v. Chungai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. In Fiddes v. Baird, 30 USPQ2d 1481, 1483, claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
The University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404, 1405 held that: …To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that “the inventor invented the claimed invention.” Lockwood v. American Airlines Inc. 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) ("[T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus an Applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2dat1966.
MPEP § 2163.02 states, “[a]n objective standard for determining compliance with the written description requirement is, 'does the description clearly allow person of ordinary skill in the art to recognize that he or she invented what is claimed’”. The courts have decided: the purpose of the "written description" requirement is broader than to merely explain how to "make and use"; the Applicant must convey with reasonable clarity to those skilled in the art, that as of the filing date sought, he or she was in possession of the invention. The invention is for purposes of the “written description” inquiry, whatever is now claimed. See Vas-Cath, Inc v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Federal Circuit, 1991).
Furthermore, the written description provision of 35 USC §112 is severable from its enablement provision; and adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993). And Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. Moreover, an adequate written description of the claimed invention must include sufficient description of at least a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics sufficient to show that Applicant was in possession of the claimed genus. However, factual evidence of an actual reduction to practice has not been disclosed by Applicant in the specification; nor has Applicant shown the invention was “ready for patenting” by disclosure of drawings or structural chemical formulas that show that the invention was complete; nor has the Applicant described distinguishing identifying characteristics sufficient to show that Applicant were in possession of the claimed invention at the time the application was filed.
Therefore for all these reasons the specification lacks adequate written description, and one of skill in the art cannot reasonably conclude that Applicant had possession of the claimed invention at the time the instant application was filed.
Enablement
Claims 70, 72-82, and 84-89 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 administration of the native GM-CSF peptide for treating Crohn’s disease, does not reasonably provide enablement for treating all of the encompassed disorders, treating with all of the encompassed variant peptides, or preventing IBD or related disorders with any composition. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
It is noted that MPEP 2164.03 teaches that “the amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability of the art. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). The amount of guidance or direction refers to that information in the application, as originally filed, that teaches exactly how to make or use the invention. The more that is known in the prior art about the nature of the invention, how to make, and how to use the invention, and the more predictable the art is, the less information needs to be explicitly stated in the specification. In contrast, if little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as how to make and use the invention in order to be enabling.”
Enablement is considered in view of the Wands factors (MPEP 2164.01 (A)). The factors considered when determining if the disclosure satisfies the enablement requirement and whether any necessary experimentation is undue include, but are not limited to (In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)):
1) nature of the invention;
2) the breadth of the claims;
3) the state of the prior art;
4) the level of one of ordinary skill;
5) the level of predictability in the art;
6) the amount of direction or guidance provided by the inventor;
7) the existence of working examples; and
8) the quantity of experimentation needed to make or use the invention based on the content of the disclosure.
1) nature of the invention; 2) the breadth of the claims;
The instant claims are directed to a method of preventing or treating one or both of an inflammatory bowel disease (IBD) and a condition resulting from IBD in a subject comprising selecting the subject having or at risk of having the IBD and administering a GM-CSF protein to the subject under conditions effective to prevent or treat one or both conditions. The GMCSF can be glycosylated or non-glycosylated, and can be administered in a number of routes. The subject can be selected based on the presence of anti-GMCSF autoantibodies in a sample from the subject, and an additional therapeutic can be administered.
The specification indicates that the term “GM-CSF protein” encompasses any number of alterations of any locations in the protein, without limit. For example, paragraph [0050] states that “once nucleic acid sequence and/or amino acid sequence information is available for a native protein (e.g. a native GM-CSF protein), a variety of techniques become available for producing virtually any mutation in the native sequences.” Paragraph [0051] states that “Mutants of a naturally occurring GM-CSF may be desirable in a variety of circumstances.” Paragraph [0052] states that “The present disclosure, in one embodiment, may relate to polypeptides with conservative amino acid substitutions, insertions, and/or deletions with respect to the mature native GM-CSF sequence.” Therefore, the specification encompasses any GM-CSF with any number of mutations, additions, or deletions, in any location in the protein. One example of a precursor GM-CSF protein found in the art (see Guyon et al (WO 2009/152944 A1; filed 5/29/09; published 12/23/09; as discussed below) has approximately 144 amino acids, and the mature protein has approximately 127 amino acids. Mutation of any two amino acids within these proteins can produce over 36,000 proteins. This level of variation is only for two mutations. If 5 mutations are selected, over 400 million proteins can be created. Therefore, the genus of encompassed GMCSF proteins is overly broad.
Further, Applicant has only defined the encompassed subjects as “having or at risk of having the IBD,” without defining any criteria that would indicate that a subject was “at risk”. Without criteria for identifying such subject, it is impossible to practice the claimed method without undue experimentation to identify the proper subjects. Also, the “conditions effective to prevent or treat one or both of the IBD and a condition resulting from the IBD” but do not identify such conditions. There are no criteria provided to define a condition to be considered “resulting from the IBD”. Therefore it is impossible to identify the subjects encompassed by the claimed method. Therefore, an overly broad genus of disorders and subjects are encompassed by the claims. The breadth of the claim exacerbates the complex nature of the subject matter to which the present claims are directed.
3) the state of the prior art; 5) the level of predictability in the art;
The prior art shows that both identifying a protein therapeutic and treating IBD or related conditions is highly unpredictable.
Protein chemistry is one of the most unpredictable areas of biotechnology. This unpredictability prevents prediction of the effects that a given number or location of mutation will have on a protein (such as TNF or a cytokine) As taught by Skolnick et al (Trends Biotechnol. 2000 Jan;18(1):34-9), sequence based methods for predicting protein function are inadequate because of the multifunctional nature of proteins (see e.g. abstract). Further, just knowing the structure of the protein is also insufficient for prediction of functional sites (see e.g. abstract). Sequence to function methods cannot specifically identify complexities for proteins, such as gain and loss of function during evolution, or multiple functions possible within a cells (see e.g. page 34, right column). Skolnick advocates determining the structure of the protein, then identifying the functionally important residues since using the chemical structure to identify functional sites is more in line with how a protein actually works (see e.g. page 34, right column).
The sensitivity of proteins to alterations of even a single amino acid in a sequence are exemplified by Burgess et al. (J. Cell Biol. 111:2129-2138, 1990) who teach that replacement of a single lysine reside at position 118 of acidic fibroblast growth factor by glutamic acid led to the substantial loss of heparin binding, receptor binding and biological activity of the protein and by Lazar et al. (Mol. Cell. Biol., 8:1247-1252, 1988) who teach that in transforming growth factor alpha, replacement of aspartic acid at position 47 with alanine or asparagine did not affect biological activity while replacement with serine or glutamic acid sharply reduced the biological activity of the mitogen. These references demonstrate that even a single amino acid substitution will often dramatically affect the biological activity and characteristics of a protein.
Further, Miosge (Proc Natl Acad Sci U S A. 2015 Sep 15;112(37):E5189-98) teach that Short of mutational studies of all possible amino acid substitutions for a protein, coupled with comprehensive
functional assays, the sheer number and diversity of missense mutations that are possible for proteins means that their functional importance must presently be addressed primarily by computational inference (see e.g. page E5189, left column). However, in a study examining some of these methods, Miosge shows that there is potential for incorrect calling of mutations (see e.g. page E5196, left column, top paragraph). The authors conclude that the discordance between predicted and actual effect of missense mutations creates the potential for many false conclusions in clinical settings where sequencing is performed to detect disease-causing mutations (see e.g. page E5195, right column, last paragraph). The findings in their study show underscore the importance of interpreting variation by direct experimental measurement of the consequences of a candidate mutation, using as sensitive and specific an assay as possible (see e.g. page E5197, left column, top paragraph). Additionally, Bork (Genome Research, 2000,10:398-400) clearly teaches the pitfalls associated with comparative sequence analysis for predicting protein function because of the known error margins for high-throughput computational methods. Bork specifically teaches that computational sequence analysis is far from perfect, despite the fact that sequencing itself is highly automated and accurate (p. 398, column 1). One of the reasons for the inaccuracy is that the quality of data in public sequence databases is still insufficient. This is particularly true for data on protein function. Protein function is context dependent, and both molecular and cellular aspects have to be considered (p. 398, column 2). Conclusions from the comparison analysis are often stretched with regard to protein products (p. 398, column 3). Further, although gene annotation via sequence database searches is already a routine job, even here the error rate is considerable (p. 399, column 2). Most features predicted with an accuracy of greater than 70% are of structural nature and, at best, only indirectly imply a certain functionality (see legend for table 1, page 399). As more sequences are added and as errors accumulate and propagate it becomes more difficult to infer correct function from the many possibilities revealed by database search (p. 399, paragraph bridging columns 2 and 3). The reference finally cautions that although the current methods seem to capture important features and explain general trends, 30% of those features are missing or predicted wrongly. This has to be kept in mind when processing the results further (p. 400, paragraph bridging cols 1 and 2).
One key issue is the prediction of protein function based on sequence similarity, which could be one way to identify the functional protein variants that are useful in the instant claims. Kulmanov et al (Bioinformatics, 34(4), 2018, 660–668), teach that there are key challenges for protein function prediction methods (see e.g. page 661, left column). These challenges arise from the difficulty identifying and accounting for the complex relationship between protein sequence structure and function (see e.g. page 661, left column). Despite significant progress in the past years in protein structure prediction, it still requires large efforts to predict protein structure with sufficient quality to be useful in function prediction (see e.g. page 661, left column). Another challenge is that proteins do not function in isolation. In particular higher level physiological functions that go beyond simple molecular interactions will require other proteins and cannot usually be predicted by considering a single protein in isolation (see e.g. page 661, left column). Due to these challenges it is not obvious what kinds of features should be used to predict the functions of a protein and whether they can be generated efficiently for a large number of proteins, such as the vast genus of GMCSF proteins encompassed by the instant claims (see e.g. page 661, left column).
Predicting whether or not an agent will be able to treat a particular disease is fraught with obstacles, even if the patient population has a well-understood disease. As taught by Ma (Modern Drug Discovery 2004, 7(6)), any results from in vitro screening often poorly correlate with in vivo results because the complicated physiological environment is absent in the in vitro system (see page 30, left column).
In addition, predicting the success of a treatment for inflammatory disease presents challenges beyond initial screening. For example, regarding autoimmune disease, according to Steinman et al (Nat Med. 2012 Jan 6;18(1):59-65), there are no approved clinical tests that are effective at predicting the therapeutic success or toxicity of treatments for autoimmune diseases (see page 59). Further Steinman et al teach that a single therapeutic strategy is probably not suitable for all autoimmune diseases or even for individual subsets of patients within one diagnostic category, as there may be heterogeneous biology underlying some of these clinical entities (see page 61). Steinman et al give the example of biologics targeting TNF and its receptors, which are effective in rheumatoid arthritis, Crohn's disease and psoriasis, but which cause marked worsening of disease in multiple sclerosis (see page 60). Blumberg et al (Nat Med.; 18(1): 35–41) teach that one of the greatest problems in translating therapies into clinical practice in autoimmunity are the numerous failures that have been the results of clinical trials. Despite the rapid progress that has been made in understanding the immune system, most of the underlying data has come from animal models, which necessarily only partially represent what is observed in humans. To compound this limitation, there exists no standardized definition of the normal human immune system, no comprehensive understanding of how this normal system is altered in autoimmune diseases and no understanding of the relationship between these immunophenotypic characteristics and either the genetic composition of the host or the environmental stimuli that either promote or protect from the development of autoimmunity (see pages 1-3).
For inflammatory bowel disease in particular, Hafez (World J Methodol 2025 December 20; 15(4): 107643) teaches that IBD is primarily comprised of CD and UC (see e.g. Hafez page 2). These conditions are characterized by persistent inflammation of the gastrointestinal tract, significantly affecting patients’ daily lives (see e.g. Hafez page 2). Despite recent developments in treatment options, including small molecules targeting various inflammatory pathways, many patients still experience treatment failures or reduced responses over time (see e.g. Hafez page 3). Therapies for IBD face significant challenges for their effectiveness (see e.g. Hafez page 3). While biologics and small-molecule treatments have revolutionized IBD control, many patients do not benefit from initial treatment (see e.g. Hafez page 3). Furthermore, secondary loss of response is common, as almost half of the patients who initially respond to biologics eventually experience treatment failure over time, complicating long-term management (see e.g. Hafez page 3). The effectiveness of biologics can vary widely among different patient groups depending on many factors, such as the type of disease, whether it is CD or UC (see e.g. Hafez page 4). Additionally, effectiveness and safety may be influenced by a patient’s genetics, medical and family history, compliance, and response to treatment (see e.g. Hafez page 4). The teachings of Hafez therefore demonstrates the unpredictability in selecting patients for treatment, and in achieving successful therapeutic benefit.
Appiah et al (J. Clin. Med. 2025, 14, 6119) teaches that the treatment of IBD has traditionally involved corticosteroids, immunosuppressants, and 5-aminosalicylates (see e.g. Appiah page 2). Biologic therapies have significantly changed the landscape of treatment for moderate-to-severe disease, particularly in patients who are refractory to conventional therapies (see e.g. Appiah page 2). However, these treatments are associated with many limitations, including high costs, side effects, and loss of efficacy over time (see e.g. Appiah page 2). Importantly, even with established therapy, primary non-response rates remain at 30–40% (see e.g. Appiah page 2). Despite advances in IBD research, important challenges persist in therapy, including with biological molecules (see e.g. Appiah page 6). These include substantial variability in patient response patterns, with individual patients demonstrating different response kinetics and durability even within the same therapeutic class (see e.g. Appiah page 6). The risk of immunogenicity remains a concern across all biologic agents, potentially leading to loss of efficacy and requiring ongoing monitoring and management strategies (see e.g. Appiah page 6).
This unpredictability is further exacerbated by lack of understanding of the causative factors for IBD, which impacts the ability of medical providers to prevent IBD or related conditions. For example, Ho et al (Inflamm Bowel Dis, Volume 25, Number S2, June 2019) teaches that the causative factors for IBD are not fully understood (see e.g. Ho, page S13). Two fundamental questions about Crohn’s disease (CD)
and ulcerative colitis (UC) that have yet to be answered are what causes the disease and, once the disease is in remission with medical or surgical therapy, what causes the disease to relapse (see e.g. Ho, page S14). The importance of genetic susceptibility has been established in the last decade and genetic risk variants have been identified, but the lack of complete gene penetrance and the rapid rise of IBD incidence in certain geographic regions suggest that the interaction between genetic and environmental factors contributes to IBD (see e.g. Ho, page S13). Without understanding the causative nature of IBD, the identification of preventative therapies is highly unpredictable.
6) the amount of direction or guidance provided by the inventor; 7) the existence of working examples;
Applicant has provided Examples 1-7, which provided in vitro experiments using blood samples, intestinal resection samples and isolated PBMCs for examining expression of anti-GMCSF autoantibodies in IBD patients, in vitro neutralizing capacity of CD-associated anti-GM-CSF autoantibodies, correlation of CD-associated anti-GMCSF autoantibodies with onset of severe disease, functions of GM-CSF in in vitro myeloid cells, and demonstration that enzymatically treated GMCSF that causes loss of post-translational modifications is capable of evading neutralizing effect of anti-GMCSF autoantibodies in vitro. However, no examples demonstrate administration of any GMCSF protein to any individual for therapeutic purposes. There are no in vivo studies to show that the in vitro molecular effects translate to in vivo therapy for IBD or related diseases. There is also no demonstration of a preventative effect of GMCSF either in vitro or in vivo. One of skill in the art would therefore be required to first screen for GMCSF variants that could potentially treat a disease, then screen to match the GMCSF to an appropriate disease, which would be undue experimentation to practice the invention.
As discussed below, Lee et al (WO 2007/009208 A1; filed 6/2/06; published 1/25/07) teaches non-glycosylated human GM-CSF having a single polyethylene glycol molecule attached through an N-terminal amino acid (see e.g. abstract). The PEG-GM-CSF can be used to treat Crohn’s disease (see e.g. page 11, first full paragraph). Therefore, the embodiment of administration of native GMCSF protein to treat Crohn’s disease is enabled. No other embodiment has been demonstrated to be enabled.
In conclusion, the claimed invention does not provide enablement for the entire scope of the claimed invention. Thus for the reasons outlined above, the specification is not considered to be enabling for one skilled in the art to make and use the claimed invention as the amount of experimentation required is undue, due to the broad scope of the claims, the lack of guidance and working examples provided in the specification. Therefore, the specification is not representative of the instant claims and the specification is not fully enabled for the instant claims. In view of the above, one of skill in the art would be forced into undue experimentation to practice the claimed invention.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 70, 72-82, and 84-89 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 70 recites a “GM-CSF protein”, which renders the claim indefinite. The specification indicates that the term “GM-CSF protein” encompassed any number of alterations of any locations in the protein, without limit. For example, paragraph [0050] states that “once nucleic acid sequence and/or amino acid sequence information is available for a native protein (e.g. a native GM-CSF protein), a variety of techniques become available for producing virtually any mutation in the native sequences.” Paragraph [0051] states that “Mutants of a naturally occurring GM-CSF may be desirable in a variety of circumstances.” Paragraph [0052] states that “The present disclosure, in one embodiment, may relate to polypeptides with conservative amino acid substitutions, insertions, and/or deletions with respect to the mature native GM-CSF sequence.” However, it is impossible to determine from the specification what amount of sequence identity, or number of substitutions are acceptable to still be encompassed by the term " GM-CSF protein”. For example, if every single amino acid were variant from the GM-CSF, this structure, while having nothing in common with the parent molecule, would still be encompassed in the instant claims.
In claims 70 and 84, the claims recite “a condition resulting from the IBD” but does not provide any criteria to define these disorders. The scope of the encompassed disorders is therefore indefinite.
In claim 70, the claim recites “a subject…at risk of having the IBD” without defining the required risk factors that would identify the encompassed subjects. The scope of the encompassed subjects is therefore indefinite.
In claims 73-79 and 87, the amino acid substitutions are identified by a specific number location in a parent sequence. However, there is no parent sequence provided to identify the location of the mutation, rendering the scope of the encompassed proteins indefinite. Further, the specification indicates that the term “GM-CSF protein” encompassed any number of alterations of any locations in the protein, without limit. For example, paragraph [0050] states that “once nucleic acid sequence and/or amino acid sequence information is available for a native protein (e.g. a native GM-CSF protein), a variety of techniques become available for producing virtually any mutation in the native sequences.” Paragraph [0051] states that “Mutants of a naturally occurring GM-CSF may be desirable in a variety of circumstances.” Paragraph [0052] states that “The present disclosure, in one embodiment, may relate to polypeptides with conservative amino acid substitutions, insertions, and/or deletions with respect to the mature native GM-CSF sequence.” If one were to delete or add amino acids, the exact location of the required modifications would be called into question, since the numbering of the amino acids would change. Therefore it is impossible to determine which locations would have the required substitutions, resulting in an indefinite claim scope.
Claim 85 recites “having detected” the presence of autoantibodies, which is a past event. However, base claim 70 requires a current “selecting” event. It is impossible to have both a past measurement and a current selection requirement.
Claims depending from the rejected claims do not remedy the deficiency and therefore are also rejected.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 70, 72, 80-82, and 89 is/are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by Lee et al (WO 2007/009208 A1; filed 6/2/06; published 1/25/07).
Instant claim 70 is directed to a method of preventing or treating one or both of an inflammatory bowel disease (IBD) and a condition resulting from the IBD in a subject comprising: selecting a subject having or at risk of having the IBD and administering a Granulocyte Macrophage-Colony Stimulating Factor (GM-CSF) protein to the selected subject under conditions effective to prevent or treat one or both of the IBD and a condition resulting from the IBD in the subject.
Instant claim 72 is directed to the method of claim 70, wherein the GM-CSF protein is not glycosylated.
Instant claim 73 is directed to the method of claim 70, wherein the GM-CSF comprises an amino acid substitution at S22.
Instant claim 74 is directed to the method of claim 70, wherein the GM-CSF comprises an amino acid substitution at S24.
Instant claim 75 is directed to the method of claim 70, wherein the GM-CSF comprises an amino acid substitution at T27.
Instant claim 76 is directed to the method of claim 70, wherein the GM-CSF comprises an amino acid substitution at S26.
Instant claim 77 is directed to the method of claim 70, wherein the GM-CSF comprises an amino acid substitution at N44.
Instant claim 78 is directed to the method of claim 70, wherein the GM-CSF comprises an amino acid substitution at N54.
Instant claim 79 is directed to the method of claim 70, wherein the GM-CSF comprises an alanine substitution at one or more of S22, S24, T27, S26, N44, and N54.
Instant claim 80 is directed to the method of claim 70, wherein the administering comprises inhalation, intranasal instillation, topically, transdermally, intradermally, parenterally, subcutaneously, intravenous injection, intra-arterial injection, intramuscular injection, intrapleurally, intraperitoneally, intrathecally, or application to a mucus membrane.
Instant claim 81 is directed to the method of claim 70, wherein the administering comprises administering a pharmaceutical composition, wherein the pharmaceutical composition comprises the GM-CSF and a pharmaceutically acceptable carrier.
Instant claim 82 is directed to the method of claim 70, wherein the IBD is Crohn's disease.
Instant claim 84 is directed to the method of claim 70, further comprising administering to the subject one or more additional agent that prevents or treats the IBD and/or a condition resulting from the IBD, wherein the additional agent is selected from an antibiotic, an anti-inflammatory, or an immunosuppressant.
Instant claim 85 is directed to the method of claim 70, wherein the selecting comprises detecting or having detected the presence of anti-GM-CSF autoantibodies in a sample from the subject.
Instant claim 86 is directed to the method of claim 85, wherein the sample is selected from whole blood, serum, urine, and nasal excretion.
Instant claim 87 is directed to the method of claim 85, wherein the GM-CSF comprises an amino acid substitution at one or more of S22, S24, T27, S26, N44, and N54.
Instant claim 88 is directed to the method of claim 85, wherein the administering comprises administering a pharmaceutical composition, wherein the pharmaceutical composition comprises the GM-CSF and a pharmaceutically acceptable carrier.
Instant claim 89 is directed to the method of claim 70, wherein the IBD is Crohn's disease or ulcerative colitis.
Regarding the limitations of instant claims 70 and 72, Lee teaches non-glycosylated human GM-CSF having a single polyethylene glycol molecule attached through an N-terminal amino acid (see e.g. abstract). The PEG-GM-CSF can be used to treat Crohn’s disease (see e.g. page 11, first full paragraph).
Regarding the limitations of instant claim 80, The PEG-GM-CSF can be given through subcutaneous injection (see e.g. page 20, last paragraph)
Regarding the limitations of instant claim 81, the PEG-GM-CSF can present in a liquid or lyophilized formulation that has a buffer (see e.g. page 9, last paragraph).
Regarding the limitations of instant claim 82 and 89, the PEG-GM-CSF can be used to treat Crohn’s disease (see e.g. page 11, first full paragraph).
Claim(s) 70, 72, 80-82, and 89 is/are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by Guyon et al (WO 2009/152944 A1; filed 5/29/09; published 12/23/09).
Instant claim 70 is directed to a method of preventing or treating one or both of an inflammatory bowel disease (IBD) and a condition resulting from the IBD in a subject comprising: selecting a subject having or at risk of having the IBD and administering a Granulocyte Macrophage-Colony Stimulating Factor (GM-CSF) protein to the selected subject under conditions effective to prevent or treat one or both of the IBD and a condition resulting from the IBD in the subject.
Instant claim 72 is directed to the method of claim 70, wherein the GM-CSF protein is not glycosylated.
Instant claim 73 is directed to the method of claim 70, wherein the GM-CSF comprises an amino acid substitution at S22.
Instant claim 74 is directed to the method of claim 70, wherein the GM-CSF comprises an amino acid substitution at S24.
Instant claim 75 is directed to the method of claim 70, wherein the GM-CSF comprises an amino acid substitution at T27.
Instant claim 76 is directed to the method of claim 70, wherein the GM-CSF comprises an amino acid substitution at S26.
Instant claim 77 is directed to the method of claim 70, wherein the GM-CSF comprises an amino acid substitution at N44.
Instant claim 78 is directed to the method of claim 70, wherein the GM-CSF comprises an amino acid substitution at N54.
Instant claim 79 is directed to the method of claim 70, wherein the GM-CSF comprises an alanine substitution at one or more of S22, S24, T27, S26, N44, and N54.
Instant claim 80 is directed to the method of claim 70, wherein the administering comprises inhalation, intranasal instillation, topically, transdermally, intradermally, parenterally, subcutaneously, intravenous injection, intra-arterial injection, intramuscular injection, intrapleurally, intraperitoneally, intrathecally, or application to a mucus membrane.
Instant claim 81 is directed to the method of claim 70, wherein the administering comprises administering a pharmaceutical composition, wherein the pharmaceutical composition comprises the GM-CSF and a pharmaceutically acceptable carrier.
Instant claim 82 is directed to the method of claim 70, wherein the IBD is Crohn's disease.
Instant claim 84 is directed to the method of claim 70, further comprising administering to the subject one or more additional agent that prevents or treats the IBD and/or a condition resulting from the IBD, wherein the additional agent is selected from an antibiotic, an anti-inflammatory, or an immunosuppressant.
Instant claim 85 is directed to the method of claim 70, wherein the selecting comprises detecting or having detected the presence of anti-GM-CSF autoantibodies in a sample from the subject.
Instant claim 86 is directed to the method of claim 85, wherein the sample is selected from whole blood, serum, urine, and nasal excretion.
Instant claim 87 is directed to the method of claim 85, wherein the GM-CSF comprises an amino acid substitution at one or more of S22, S24, T27, S26, N44, and N54.
Instant claim 88 is directed to the method of claim 85, wherein the administering comprises administering a pharmaceutical composition, wherein the pharmaceutical composition comprises the GM-CSF and a pharmaceutically acceptable carrier.
Instant claim 89 is directed to the method of claim 70, wherein the IBD is Crohn's disease or ulcerative colitis.
Regarding the limitations of instant claims 70, 82, and 89, Guyon teaches administration of non-glycosylated GM-CSF (see e.g. page 125). The instant claims encompass “preventing” inflammatory bowel disease or a condition resulting from the IBD. The term “preventing” is not defined in the specification, and therefore will be given the broadest reasonable interpretation, which includes avoiding the onset of disease. In other words, the term “preventing” includes administration to people that do not have IBD, and any administration would have the effect of prevention or treatment, depending on the disease state of the subject. Therefore the administration of Guyon reads on prevention of IBD.
Regarding the limitations of instant claim 72, Guyon teaches the GM-CSF can be non-glycosylated (see e.g. page 125, lines 25-32).
Regarding the limitations of instant claim 73-79, Guyon teaches the GM-SCF can be modified at sites S5, S7, S9, T10, N27, and/or N37 (see e.g. page 125, lines 10-25). The positions are further defined as correlating to S22, S24, S26, T27, N44 and N54 of the precursor polypeptide (see e.g. page 124 lines 25-32 and page 125, lines 1-11).
Regarding the limitations of instant claims 80, Guyon teaches the GM-CSF can be administered through routes including intravenous, topical, intraperitoneal and others (see e.g. page 190, lines 25-32 and page 191, lines 1-5).
Regarding the limitations of instant claim 81, Guyon teaches that the GM-CSF as a therapeutic polypeptide can be missed with physiologically acceptable carriers in a pharmaceutical composition (see e.g. page 190, lines 25-32).
Regarding the limitations of instant claim 84, Guyon teaches further comprising an additional therapeutic agent (see e.g. page 191, lines 1-10). For example, the combination can include anti-cancer antibiotics (see e.g. page 216, lines 1-10).
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.
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.
Claim(s) 70, 72, 80-82, 85-86, and 88-89 is/are rejected under 35 U.S.C. 103 as being unpatentable over Lee et al (WO 2007/009208 A1; filed 6/2/06; published 1/25/07) in view of Wang et al (Proc Natl Acad Sci U S A. 2013 May 7;110(19):7832-7).
Instant claim 70 is directed to a method of preventing or treating one or both of an inflammatory bowel disease (IBD) and a condition resulting from the IBD in a subject comprising: selecting a subject having or at risk of having the IBD and administering a Granulocyte Macrophage-Colony Stimulating Factor (GM-CSF) protein to the selected subject under conditions effective to prevent or treat one or both of the IBD and a condition resulting from the IBD in the subject.
Instant claim 72 is directed to the method of claim 70, wherein the GM-CSF protein is not glycosylated.
Instant claim 73 is directed to the method of claim 70, wherein the GM-CSF comprises an amino acid substitution at S22.
Instant claim 74 is directed to the method of claim 70, wherein the GM-CSF comprises an amino acid substitution at S24.
Instant claim 75 is directed to the method of claim 70, wherein the GM-CSF comprises an amino acid substitution at T27.
Instant claim 76 is directed to the method of claim 70, wherein the GM-CSF comprises an amino acid substitution at S26.
Instant claim 77 is directed to the method of claim 70, wherein the GM-CSF comprises an amino acid substitution at N44.
Instant claim 78 is directed to the method of claim 70, wherein the GM-CSF comprises an amino acid substitution at N54.
Instant claim 79 is directed to the method of claim 70, wherein the GM-CSF comprises an alanine substitution at one or more of S22, S24, T27, S26, N44, and N54.
Instant claim 80 is directed to the method of claim 70, wherein the administering comprises inhalation, intranasal instillation, topically, transdermally, intradermally, parenterally, subcutaneously, intravenous injection, intra-arterial injection, intramuscular injection, intrapleurally, intraperitoneally, intrathecally, or application to a mucus membrane.
Instant claim 81 is directed to the method of claim 70, wherein the administering comprises administering a pharmaceutical composition, wherein the pharmaceutical composition comprises the GM-CSF and a pharmaceutically acceptable carrier.
Instant claim 82 is directed to the method of claim 70, wherein the IBD is Crohn's disease.
Instant claim 84 is directed to the method of claim 70, further comprising administering to the subject one or more additional agent that prevents or treats the IBD and/or a condition resulting from the IBD, wherein the additional agent is selected from an antibiotic, an anti-inflammatory, or an immunosuppressant.
Instant claim 85 is directed to the method of claim 70, wherein the selecting comprises detecting or having detected the presence of anti-GM-CSF autoantibodies in a sample from the subject.
Instant claim 86 is directed to the method of claim 85, wherein the sample is selected from whole blood, serum, urine, and nasal excretion.
Instant claim 87 is directed to the method of claim 85, wherein the GM-CSF comprises an amino acid substitution at one or more of S22, S24, T27, S26, N44, and N54.
Instant claim 88 is directed to the method of claim 85, wherein the administering comprises administering a pharmaceutical composition, wherein the pharmaceutical composition comprises the GM-CSF and a pharmaceutically acceptable carrier.
Instant claim 89 is directed to the method of claim 70, wherein the IBD is Crohn's disease or ulcerative colitis.
Regarding the limitations of instant claims 70 and 72, Lee teaches non-glycosylated human GM-CSF having a single polyethylene glycol molecule attached through an N-terminal amino acid (see e.g. abstract). The PEG-GM-CSF can be used to treat Crohn’s disease (see e.g. page 11, first full paragraph).
Regarding the limitations of instant claim 80, Lee teaches the PEG-GM-CSF can be given through subcutaneous injection (see e.g. page 20, last paragraph)
Regarding the limitations of instant claim 81, Lee teaches the PEG-GM-CSF can present in a liquid or lyophilized formulation that has a buffer (see e.g. page 9, last paragraph).
Regarding the limitations of instant claim 82 and 89, Lee teaches the PEG-GM-CSF can be used to treat Crohn’s disease (see e.g. page 11, first full paragraph).
Lee does not teach detection of GM-CSF autoantibodies for selecting the subject.
Wang teaches measurement of anti-GM-CSF autoantibodies (see e.g. abstract). Wang teaches that all autoantibodies neutralized GM-CSF bioactivity (see e.g. abstract). Wang teaches that autoantibodies that potentially neutralize GM-CSF may be useful for treating inflammatory disease (see e.g. abstract). Wang extracts the samples from whole blood (see e.g. page 7836, right column).
It would have been obvious to one with ordinary skill in the art, at the time of the invention, to select patients with anti-GMCSF autoantibodies for treatment because according to Wang, anti-GMCSF autoantibodies are expected to be helpful for treating autoimmune disease. The Supreme Court set forth in KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), that if the scope and content of the prior art included a similar or analogous product, with differences between the claimed invention and prior art that were encompassed in known variation or in a principle known in the art, and one of ordinary skill in the art could have combined the elements as claimed by known methods, the claimed variation would have been predictable in to one of ordinary skill in the art. The method of Lee treats an autoimmune disorders, including Crohn’s disease. Treating patients that possessed anti-GMCSF, which could potentially lower autoimmune disease as taught in Wang, with the administration of non-glycosylated GM-CSF that has decreased immunogenicity as taught in Lee (see e.g. page 2) would fall within a known variation of the art that would be reasonably predictable to one of skill in the art.
Moreover, the instant situation is amenable to the type of analysis set forth in In re Kerkhoven, 205 USPQ 1069 (CCPA 1980) wherein the court held that it is prima facie obvious to combine two treatments, each of which is taught by the prior art to be useful for the very same purpose. The idea of combining them flows logically from having been individually taught in the prior art. Applying the same logic to the instant claims, one of ordinary skill in the art would have been imbued with at least a reasonable expectation of success that ensuring that the patient has both the anti-GM-CSF autoantibodies and the non-glycosylated GM-CSF with the lowered immunogenicity, would result in a combined therapeutic effect.
Conclusion
No claim is allowed.
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/ANDREA K MCCOLLUM/Examiner, Art Unit 1674