DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The instant application, filed October 6, 2023, is a 371 of International Application No. PCT/KR2022/004614, filed on March 31, 2022, which was published as International Application Publication No. WO 2022/215949 A1. The instant application claims foreign priority to an application filed in the Republic of Korea, Korean Patent Application No. KR10-2021-0044582, filed on April 6, 2021. Receipt is acknowledged of a certified copy of the foreign priority application. A certified copy of the translation of the foreign priority application has not been received.
Status of Claims
Pursuant to a Preliminary Amendment dated October 6, 2023, claims 1-12 are pending, claims 1-8 are amended, and claims 13-19 are canceled.
Information Disclosure Statement
The Information Disclosure Statement (“IDS”) submitted on October 6, 2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Specification Objections
The specification (including the abstract and claims), and any amendments for applications, except as provided for in 37 CFR 1.821 through 1.825, must have text written plainly and legibly either by a typewriter or machine printer in a nonscript type font (e.g., Arial, Times Roman, or Courier, preferably a font size of 12) lettering style having capital letters which should be at least 0.3175 cm. (0.125 inch) high, but may be no smaller than 0.21 cm. (0.08 inch) high (e.g., a font size of 6) in portrait orientation and presented in a form having sufficient clarity and contrast between the paper and the writing thereon to permit the direct reproduction of readily legible copies in any number by use of photographic, electrostatic, photo-offset, and microfilming processes and electronic capture by use of digital imaging and optical character recognition; and only a single column of text. See 37 CFR 1.52(a) and (b).
The application papers are objected to because Tables 2-8 are unclear and are therefore illegible. A legible substitute specification in compliance with 37 CFR 1.52(a) and (b) and 1.125 is required.
Claim Interpretation
Background
The instant claims are generally directed to uses of the compound (R)-4-{(R)-1-[7-(3,4,5-trimethoxy-phenyl)-[1,6] naphthyridine-5-yloxy]-ethyl}pyrrolidine-2-one in the field of diabetes treatments. The Specification provides the following structure for the aforementioned compound (however, nota bene the following footnote and the section below regarding 35 USC § 112(d)):
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Specification at 16-17.1
The Specification refers to the compound named above using its pharmaceutical compound number, BI-1002494. See, e.g., Specification at 20, Example 1 (assigning the pharmaceutical compound number BI-1002494 to the compound named above). For consistency, the examiner will use the same nomenclature to refer to the compound named above.
“Treating”
Independent claim 1 and its dependent claims 2-8 are generally directed to a method of “treating” diabetes. The Specification does not set forth a special definition for the claim term “treating”. As used in claims 1-8, the claim term “treating” is the present participle of the verb “treat”, which is also not defined in the Specification. However, as explained below, the Specification does set forth a special definition for the term “treatment”, whereby it defines treatment in terms of the symptoms of metabolic disease. As explained below, the scope of a method of “treating” diabetes is broader than the “treatment” of diabetes.
Pending claims are given their broadest reasonable interpretation consistent with the specification. See MPEP 2111. “Under a broadest reasonable interpretation (BRI), words of the claim must be given their plain meaning, unless such meaning is inconsistent with the specification. The plain meaning of a term means the ordinary and customary meaning given to the term by those of ordinary skill in the art at the relevant time.” MPEP 2111.01(I).
Prior art may provide the plain meaning of a claim term:
In some cases it is also appropriate to look to how the claim term is used in the prior art, which includes prior art patents, published applications, trade publications, and dictionaries. Phillips v. AWH Corp., 415 F.3d 1303, 1317, 75 USPQ2d 1321, 1329 (Fed. Cir. 2005) ("Although we have emphasized the importance of intrinsic evidence in claim construction, we have also authorized district courts to rely on extrinsic evidence, which "consists of all evidence external to the patent and prosecution history, including expert and inventor testimony, dictionaries, and learned treatises.")
MPEP 2111.01(III).
However, note that:
The only exceptions to giving the words in a claim their ordinary and customary meaning in the art are (1) when the applicant acts as their own lexicographer; and (2) when the applicant disavows or disclaims the full scope of a claim term in the specification. To act as their own lexicographer, the applicant must clearly set forth a special definition of a claim term in the specification that differs from the plain and ordinary meaning it would otherwise possess.
MPEP 2111.01(IV).
Turning to the Specification, it defines “treatment” as “all actions that improve or beneficially change the symptoms of metabolic disease by administering the composition of the present disclosure.” Specification at 12 (emphasis added).
The Specification does not provide a special definition of term “the symptoms of metabolic disease”, and instead provides examples of symptoms that diabetes, a metabolic disease, exhibits. See, e.g., Specification at 2-3 (“The diabetes exhibits characteristic symptoms of hyperglycemia are displayed due to abnormal physiological metabolic control functions, such as carbohydrate, protein, lipid and electrolyte metabolisms due to hormonal imbalance including insulin (Gonuth, S.M., Ann. Intern. Med. , 79, pp812-822, 1973). When these hyperglycemia symptoms persist, the symptoms cause blood circulation disorders, retinal damage, nerve cell damage, decreased kidney function, and vascular complications (UK Prospective Diabetes Study (UKPDS) Group, Lancet, 352, pp837853, 1998).”). Specification at 2-3.
Because the Specification sets forth a special definition for the term “treatment”, and not the term “treating”, the broadest reasonable interpretation of the claim term “treating” must be its plain meaning consistent with the Specification. As mentioned above, the claim term “treating” as used in claims 1-8 is the present participle of the verb “treat”.
According to the Oxford Dictionary of English (3 ed. 2015), attached hereto, the verb “treat” in the context of medicine means “give medical care or attention to; try to heal or cure”.
A method of giving medical care or attention to, or trying to heal or cure diabetes, includes treating the symptoms of diabetes ,and treating the complications of diabetes.
Moreover, it is well known that the complications of diabetes often are the presenting symptoms that lead to diagnosis of diabetes. See Max Ellenberg, “Diabetic Complications Without Manifest Diabetes – Complications as Presenting Clinical Symptoms”, JAMA, vol. 183, no. 11, pp. 926-930 (1963), hereinafter “Ellenberg 1963”, at Abstract:
A number of conditions generally recognized as complications of diabetes mellitus frequently occur before the characteristic findings of hyperglycemia, glycosuria, polyuria, and polyphagia. As a result, the complications appear as the presenting symptoms that lead to the diagnosis. The characteristic retinopathy, for example, occasionally causes impairment of vision before glycosuria is found. This fact, that characteristic disorders can involve the eye, the skin, the nervous and vascular systems, the kidney, and the reproductive functions before the characteristic disorder of carbohydrate metabolism becomes manifest, means that diabetes mellitus is a complex disease. It should no longer be thought of as meaning simply hyperglycemia and glycosuria. An alert clinician has the opportunity to recognize the disease more promptly, begin its management at an earlier stage, and solve some obscure clinical problems.
Ellenberg 1963 at Abstract.
Therefore, the examiner interprets scope of claim 1 and its dependent claims as covering methods of treating the symptoms of diabetes and methods of treating the complications of diabetes.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 2 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 1 is directed to a method of treating diabetes, comprising administering (R)-4-{(R)-1-[7-(3,4,5-trimethoxy-phenyl)-[1,6] naphthyridine-5-yloxy]-ethyl}pyrrolidine-2-one or a pharmaceutically acceptable salt thereof as an active ingredient to a subject in need thereof.
Claim 2 recites the method of claim 1, and provides a structure of the compound that claim 1 recites, which is reproduced below.
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Claim 2.
One having ordinary skill in the art at the time of filing would not equate the chemical named in claim 1 with the structure provided in claim 2 because both chiral sites that the chemical name requires are not indicated. The structure provided in claim 2 instead implies a racemic mixture of diastereomers.2
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
Claims 1 and 3-5 are Obvious over Arthur 2013 in view of van Eeuwijk 2016
Claims 1 and 3-5 are rejected under 35 U.S.C. 103 as being unpatentable over J. F. Arthur et al., “Exacerbation of Glycoprotein VI-Dependent Platelet Responses in a Rhesus Monkey Model of Type 1 Diabetes”, Journal of Diabetes Research, vol. 2013, no. 1, pp. 1-9 (2013), hereinafter “Arthur 2013”, in view of van Eeuwijk, Judith MM et al., "The Novel Oral Syk Inhibitor, BI1002494, Protects Mice from Arterial Thrombosis and Thromboinflammatory Brain Infarction", Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 36, no. 6, pp. 1247-1253 (2016), hereinafter “van Eeuwijk 2016”.
Claim 1 is generally directed to a method of treating diabetes comprising administering a spleen tyrosine kinase (“SYK”) inhibitor to a subject in need thereof. In particular, applicant claims the method comprising administering the known SYK inhibitor, (R)-4-{(R)-1-[7-(3,4,5-trimethoxy-phenyl)-[1,6] naphthyridine-5-yloxy]-ethyl}pyrrolidine-2-one.
As discussed above in the section regarding claim interpretation, the Specification discloses that BI-1002494 is the compound named in claim 1. See, e.g., Specification at 20, example 1 (assigning the pharmaceutical compound number BI-1002494 to the chemical name recited in claim 1).
Background: WO’128 and BI-1002494
As background, reference is made to Hoffmann et al., “Substituted Naphthyridines and their Use as SYK Kinase Inhibitors”, International Publication No. WO 2011/092128 A1, published on August 4, 2011, hereinafter “WO’128”.3
BI-1002494 was disclosed in WO’128 as example 35. See, e.g., WO’128 at 110-111 (describing the synthesis of BI-1002494, which is excerpted below).4
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WO’128 at 110-111 (excerpted to remove blank space between pages).
WO’128 discloses that compounds of the invention, including BI-1002494, are “suitable as SYK inhibitors”, WO’128 at 118, and reports that BI-1002494 inhibits SYK with an IC50 of 0.0002 μM, WO’128 at 128. “SYK” is an abbreviation for a particular protein kinase named spleen tyrosine kinase. Id. at 2.
SYK is an intracellular tyrosine kinase that mediates signal transduction between many cells in the immune system, and its inhibition is the therapeutic target for the treatment of many different diseases such as autoimmune disease and others that are often characterized by inflammation. See id. at 2-4.
WO’128 further discloses pharmaceutical compositions comprising compounds of the invention, such as BI-1002494. See, e.g., WO’128 at Abstract (“The invention relates to new substituted naphthyridines of formula (1), as well as pharmacologically acceptable salts, diastereomers, enantiomers, racemates, hydrates or solvates thereof, … as well as pharmaceutical compositions containing these compounds.”); id. at 167-171 (disclosing various formulations of the disclosed active substances, i.e., the compounds of formula 1, which encompasses BI-1002494).
Arthur 2013
Arthur 2013 generally discloses treating diabetes in a subject by administering SYK inhibitors, and in particular, Arthur 2013 discloses the study of SYK inhibitors
in monkey models of diabetes as an antiplatelet therapy for diabetic patients to prevent thrombotic complications of diabetes, Arthur 2013 at Abstract, and
in mice models of diabetes to delay the onset of spontaneous diabetes in nonobese diabetic mice, and to delay the progression of early-established diabetes, Arthur 2013 at 7 (right column).
As background, Arthur 2013 explains that thrombotic complications are a major cause of death for patients with diabetes:
One of the high risk complications of diabetes is thrombosis, and platelets are pivotal to thrombus formation, particularly in arterial vessels, and hence the resultant thrombotic complications of myocardial infarction or ischaemic stroke. Platelets from individuals with diabetes, particularly Type 2 diabetes, are more sensitive to aggregation by a variety of agonists [2, 3], and 80% of diabetic patients are likely to die from thrombotic complications [4]. Considerably less is known about platelet activation in Type 1 diabetes, although the relative risk of cardiovascular disease in Type 1 diabetic patients can be as much as 10-fold greater than that in nondiabetic individuals [1].
Arthur 2013 at 1 (emphasis added).
Arthur 2013 teaches that reactive oxygen species (“ROS”) are a type of agonist that may influence platelet function, whereby they initiate a cascade that involves glycoprotein VI, that leads to the recruitment and activation of SYK, which in turn leads to platelet aggregation:
Exogenous reactive oxygen species (ROS) can influence platelet function, and platelets themselves are able to generate ROS. We have shown that the major collagen receptor on platelets, glycoprotein (GP) VI, is linked to redox signalling pathways via its association with the adaptor molecule, tumour necrosis factor receptor-associated factor 4 (TRAF4; [8]). TRAF4 interacts with an intracellular sequence of GPVI as well as p47phox of the NADPH oxidase complex, the major source of ROS in platelets. Initiation of GPVI-dependent signalling involves GPVI-associated Lyn phosphorylating an immunoreceptor tyrosine-based activation motif (ITAM) in FcRγ (in a complex with GPVI), leading to recruitment and activation of spleen tyrosine kinase (Syk). A subsequent tyrosine phosphorylation signalling cascade results in intraplatelet calcium mobilisation and activation of the integrin αIIbβ3, leading to platelet aggregation and metalloproteinase-dependent GPVI ectodomain shedding. Intracellular ROS generation following GPVI engagement is an early signalling event and precedes GPVI-dependent signalling leading to aggregation and shedding. We have recently shown that GPVI ROS generation is comprised of two phases: an initial Syk-independent burst followed by additional Syk-dependent generation [9]. In the current study, we investigate GPVI-dependent ROS generation and calcium mobilisation in a rhesus model of Type 1 diabetes. Compared with rodent models, monkeys are metabolically closer to humans, and a longer lifespan allows long-term disease progression to be assessed in the same animal over 3–5 years. Genetic variability in monkeys also better approximates disease in humans compared with in-bred rodents. Importantly, while the GPVI primary sequence and platelet immunoreceptor signalling pathways are significantly different in rats or mice compared with human, monkey GPVI is closely related [10] making them suitable for platelet functional analysis.
Arthur 2013 at 1-2 (emphasis added).
Arthur 2013 discloses GPVI-mediated ROS generation is exacerbated in poorly controlled diabetic monkeys (i.e., STZ induced diabetic monkeys receiving a reduced insulin regime):
To evaluate the effect of glucose control on early GPVI-mediated ROS generation in diabetic monkeys, we utilised a flow cytometry-based assay to rapidly assess intracellular ROS using the fluorescent dye, H2DCF-DA. Basal ROS in platelet-rich plasma (PRP) from all three monkey groups was similar (Table 1). Treatment of platelets with 10 μg/mL of the GPVI-specific agonist collagen-related peptide (CRP) for 2 min increased intraplatelet ROS in all groups, but there was a significant exacerbation of CRP-induced ROS generation in the poorly controlled diabetic monkeys (Figure 2). There was a tendency for intracellular ROS generation in the well-controlled diabetic monkeys to be lower compared with healthy or poorly controlled diabetic monkeys, but this did not achieve statistical significance (P = 0.094).
Arthur 2013 at 3-4 (emphasis added).
Arthur 2013 further discloses that inhibition of SYK with the SYK inhibitor BAY61-3606 reduced CRP-induced ROS generation:
To examine early GPVI signalling events, platelets were treated with GPVI agonist in the presence and absence of 5 μM BAY61-3606, a potent, specific inhibitor of Syk [24]. Increased DCF fluorescence in response to CRP occurs in two distinct phases: an initial burst of ROS occurring within 2 min followed by additional ROS generation as a consequence of downstream signalling [9]. Syk inhibition reduced CRP-induced ROS in all monkey groups and, critically, reduced the exacerbated ROS in poorly controlled diabetic monkeys to levels observed in healthy monkeys (Figure 2).
Arthur 2013 at 4 (emphasis added).
Figure 2 of Arthur 2013 referenced in the above passage is reproduced below :
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Arthur 2013 at 5, Figure 2.
Arthur 2013 discloses that inhibition of SYK with the SYK inhibitor BAY61-3606 reduced “GPVI-dependent ROS generation regardless of the level of glycaemic control in diabetic monkeys, indicating that Syk inhibition could prove to be an effective antiplatelet strategy for diabetic patients.” Id. at 8 (emphasis added).
Arthur 2013 further discloses studies of oral administration of the SYK inhibitor R788 in mice,5 wherein it “delayed the onset of spontaneous diabetes in nonobese diabetic (NOD) mice and the progression of early-established diabetes even when treatment was initiated after the development of glucose intolerance in those animals [41].” Id. at 7.
Arthur 2013 further remarks that, in general, SYK inhibition may be an effective strategy for preventing the complications of diabetes (e.g., arterial thrombosis):
Syk inhibition could prove to be an effective antiplatelet strategy for diabetic patients because of its minimal impact on primary haemostasis while providing significant protection from arterial thrombosis [40].
Arthur 2013 at 7.
Arthur 2013 concludes that its results “point to a potential antithrombotic therapeutic benefit of Syk inhibition in hyperglycaemic diabetes.” Arthur 2013 at Abstract.
While Arthur 2013 discloses methods of treating diabetes with SYK inhibitors, it does not disclose a method of treating diabetes with the SYK inhibitor BI-1002494.
However, one having ordinary skill in the art at the time of filing would have a reasonable expectation of success in adapting the methods of treating diabetes with SYK inhibitors disclosed in Arthur 2013 to include the alternative SYK inhibitor BI-1002494, because BI-1002494 was known to profoundly protect mice from arterial thrombosis (van Eeuwijk 2016).
van Eeuwijk 2016
van Eeuwijk 2016 generally discloses the study of BI-1002494 in mice models of arterial thrombosis.6 Similar to Arthur 2013, van Eeuwijk 2016 explains the role of SYK in platelet aggregation and, that in platelets, SYK is essential for signaling downstream of receptors such as glycoprotein VI. Id. at 1247-1248.
Regarding BI-1002494, van Eeuwijk 2016 discloses that:
[T]reat-ment with the novel selective and orally bioavailable Syk inhibitor, BI1002494, profoundly protects mice from arterial thrombosis and cerebral infarct progression while not increasing the risk of intracranial hemorrhage.
van Eeuwijk 2016 at 1248, and
Bl1002494-treated mice were subjected to mechanical injury of the aorta and found to be completely protected from vessel occlusion (Figure 6B).
Id. at 1249.
Figure 6 from van Eeuwijk 2016 is reproduced on the following page.
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van Eeuwijk 2016 at 1251, Figure 6.
Claim 1 was Obvious at the Time of Filing
One having ordinary skill in the art at the time of filing would be motivated to develop a method of treating diabetes in a subject in need thereof using a SYK inhibitor because Arthur 2013 discloses that “Syk inhibition could prove to be an effective antiplatelet strategy for diabetic patients because of its minimal impact on primary haemostasis while providing significant protection from arterial thrombosis.” Arthur 2013 at 7. One having ordinary skill in the art at the time of filing would be further motivated to treat diabetes in a subject with a focus on thrombosis because Arthur 2013 teaches that “80% of diabetic patients are likely to die from thrombotic complications.” Arthur 2013 at 1. One having ordinary skill in the art at the time of filing would have a reasonable expectation of success in selecting BI-1002494 as the SYK inhibitor because van Eeuwijk 2016 discloses that “treat-ment with the novel selective and orally bioavailable Syk inhibitor, BI1002494, profoundly protects mice from arterial thrombosis….”
Therefore, claim 1 was obvious at the time of filing.
Claim 3
Regarding claim 3, it depends upon claim 1 and recites that the diabetes is insulin-resistant diabetes.
Arthur 2013 and van Eeuwijk 2016 are relied upon as above.
Type 2 diabetes is characterized by insulin resistance. See, e.g., Specification at 2.
Arthur 2013 discloses that “[p]latelets from individuals with diabetes, particularly Type 2 diabetes, are more sensitive to aggregation by a variety of agonists [2, 3], and 80% of diabetic patients are likely to die from thrombotic complications[4].” Id. at 1.
Therefore, one having ordinary skill in the art at the time of filing would be further motivated with a reasonable expectation of success to develop a method of treating insulin-resistant diabetes (e.g., Type 2 diabetes) using a SYK inhibitor known to protect from arterial thrombosis, such as BI-1002494 as disclosed by van Eeuwijk 2016, because Arthur 2013 discloses that platelets from individuals with Type 2 diabetes are more sensitive to aggregation.
Accordingly, claim 3 was obvious at the time of filing for the reasons stated above, and for the reasons stated in claim 1.
Claim 4
Regarding claim 4, it depends upon claim 1 and recites that the diabetes is Type 1 diabetes, Type 2 diabetes, and gestational diabetes.
Arthur 2013 and van Eeuwijk 2016 are relied upon as above.
Arthur 2013 discloses that individuals with diabetes, irrespective of the particular type of diabetes, “are more sensitive to aggregation by a variety of agonists….” Arthur 2013 at 1.
Therefore, one having ordinary skill in the art at the time of filing would be further motivated with a reasonable expectation of success to develop a method of treating Type 1 diabetes, Type 2 diabetes, and gestational diabetes in a subject using a SYK inhibitor known to protect from arterial thrombosis, such as BI-1002494 as disclosed by van Eeuwijk 2016, because Arthur 2013 discloses that platelets from individuals with diabetes, irrespective of the particular type of diabetes, are more sensitive to aggregation.
Accordingly, claim 4 was obvious at the time of filing for the reasons stated above, and for the reasons stated in claim 1.
Claim 5
Claim 5 depends upon claim 1 and specifies that the subject requires reducing blood sugar.
Arthur 2013 and van Eeuwijk 2016 are relied upon as above.
A subject that is hyperglycemic may require reducing blood sugar. See, e.g., Specification at 3 (“The ultimate goal of current diabetes treatment is to continuously maintain normalization of blood sugar. This can be seen from several experimental examples that most diabetic complications are caused by metabolic failure caused by persistent hyperglycemia, and complications may be suppressed or delayed by strict blood sugar control in animals and clinical practice.”).
Arthur 2013 further discloses that its results “point to a potential antithrombotic therapeutic benefit of Syk inhibition in hyperglycaemic diabetes.” Arthur 2013 at Abstract.
Therefore, one having ordinary skill in the art would have a reasonable expectation of success in treating diabetes in a subject with SYK inhibitor BI-1002494 for the reasons stated regarding the obviousness of claim 1. One having ordinary skill in the art at the time of filing would be motivated with a reasonable expectation of success to direct such a treatment method to such a subject that further requires reducing blood sugar (e.g., because the subject is hyperglycaemic) because Arthur 2013 discloses the antithrombotic therapeutic benefit of SYK inhibition in hyperglycaemic diabetes.
Therefore, claim 5 was obvious at the time of filing.
Claim 6 is Obvious over Arthur 2013 in view of van Eeuwijk 2016, Dandona 2004 and Yang 2008
Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over Arthur 2013 in view of van Eeuwijk 2016, Dandona, Paresh, et al., "Inflammation: the link between insulin resistance, obesity and diabetes", Trends in immunology, vol. 25, no. 1, pp. 4-7 (2004), hereinafter “Dandona 2004”, and Yang, Won Seok, et al., "High glucose-induced NF-κB activation occurs via tyrosine phosphorylation of IκBα in human glomerular endothelial cells: involvement of Syk tyrosine kinase", American journal of physiology-renal physiology, vol. 294, no. 5, pp. F1065-F1075 (2008), hereinafter “Yang 2008”.
Arthur 2013 and van Eeuwijk 2016 are relied upon as above.
Claim 6 depends upon claim 1 and specifies that the subject requires reducing insulin resistance.
Arthur 2013 and van Eeuwijk 2016 do not expressly teach that administration of SYK inhibitors may reduce insulin resistance in a subject with diabetes.
However, one having ordinary skill in the art at the time of filing would have a reasonable expectation off success in reducing insulin resistance in a subject with diabetes by administration of a SYK inhibitor because 1) Yang 2008 discloses that SYK inhibition inhibits activation of NF-κB through the high glucose-induced tyrosine phosphorylation of IκBα route, and 2) Dandona 2004 explains that activation of NF-κB inhibits insulin signaling which leads to insulin resistance.
Yang 2008
As background, Yang 2008 teaches that NF-κB is implicated in the development of diabetic nephropathy through its involvement in chemokine production that leads to downstream diabetic renal injury:
THE TRANSCRIPTIONAL FACTOR nuclear factor-κB (NF-κB) is implicated in the development of diabetic nephropathy by mediating high glucose-induced cytokine production. High glucose induced CC chemokine ligand 2 (CCL2; monocyte chemoattractant protein-1) production is such an example. In the studies of cultured glomerular mesangial cells (8, 11), high glucose was shown to induce CCL2 production, in which NF-κB was the responsible transcriptional factor (8). Secreted CCL2 in vivo may cause macrophage recruitment and activation, resulting in diabetic renal injury (30).
Yang 2008 at F1065.
Yang 2008 teaches that NF-κB is typically sequestered in the cytoplasm and requires activation through serine or tyrosine phosphorylation of specific inhibitory proteins:
The major form of NF-κB is composed of a dimer of p50 and p65 subunits and is sequestered in the cytoplasm through its tight association with specific inhibitory proteins (IκB) (7). Thus NF-κB activation requires dissociation from IκB. This occurs by serine or tyrosine phosphorylation of IκBα. Serine phosphorylation leads to the degradation of IκBα by the ubiquitin-proteasome complex (4, 25). In contrast, tyrosine phosphorylation activates NF-κB without degradation of IκBα (3, 12). After dissociation from IκB, NF-κB translocates to the nucleus and binds to a specific sequence in DNA, which in turn results in gene transcription.
Yang 2008 at F1065 (emphasis added).
Yang 2008 further teaches that high glucose is known to activate NF-κB, and that glomerular endothelial cells of diabetic patients are directly exposed to high glucose.
High glucose is known to activate NF-κB via protein kinase C and reactive oxygen species (ROS).
Yang 2008 at Abstract, and
Glomerular endothelial cells are in direct contact with high glucose in the blood of diabetic patients.
Yang 2008 at F1065.
Yang 2008 discloses that high glucose induces NF-κB activation through the tyrosine phosphorylation route:
High glucose increased nuclear translocation of p65 and also increased NF-κB DNA binding activity. High glucose-induced NF-κB activation occurred without degradation of IκBα. In agreement with this, there was no increase in serine phosphorylation of IκBα, while tyrosine phosphorylation of IκBα was increased by high glucose.
Yang 2008 at Abstract (emphasis added).
Yang 2008 discloses that SYK is the tyrosine kinase primarily responsible for high glucose-induced tyrosine phosphorylation of IκBα:
To determine the tyrosine kinase responsible for high glucose-induced tyrosine phosphorylation of IκBα, the cells were left untreated or pretreated with broad-spectrum inhibitors of tyrosine kinases [genistein (50 μM), herbimycin A (1 μM)], [a specific inhibitor of Syk (BAY 61-3606; 0.1, 1, or 10 μM)] or an inhibitor of the Src family of tyrosine kinases (PP2; 1, 5, or 10 μM) for 30 min and then stimulated with high glucose. The concentrations of the inhibitors were selected based on published studies (5, 13, 31). Both genistein and herbimycin A prevented high glucose-induced nuclear translocation of p65. The inhibitory effect of PP2 on high glucose-induced nuclear translocation of p65 was small. In contrast, BAY 61-3606 almost completely inhibited high glucose-induced tyrosine phosphorylation of IκBα as well as p65 nuclear translocation (Fig. 11, A and B). To see the effects of specific suppression of Syk protein, we transfected Syk-siRNA or control-siRNA into the cells and then treated them with 5 or 30 mM glucose for 30 min. As shown in Fig. 11, C–E, Syk-siRNA effectively suppressed the expression of Syk protein and inhibited high glucose-induced tyrosine phosphorylation of IκBα and p65 nuclear translocation.
Yang 2008 at F1070 (emphases added).
Figure 11 of Yang 2008 referenced in the above passage is reproduced below:
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Yang 2008 at F1074, Figure 11.
In summary regarding SYK inhibition, Yang 2008 discloses that in vitro, “BAY 61-3606, a specific inhibitor of Syk protein-tyrosine kinase … inhibited high glucose-induced tyrosine phosphorylation of IκBα as well as p65 nuclear translocation.” Yang 2008 at Abstract.
Dandona 2004
Dandona 2004 discloses links between inflammation and the development of insulin resistance. For example, in Figure 1 (reproduced below), Dandona 2004 shows that NF-κB activates inflammatory cytokines which leads to the inhibition of insulin signaling and subsequent rise in insulin resistance.
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Dandona 2004 at 6.
Claim 6 was Obvious at the Time of Filing
One having ordinary skill in the art would have a reasonable expectation of success in treating diabetes in a subject with SYK inhibitor BI-1002494 for the reasons stated regarding the obviousness of claim 1. One having ordinary skill in the art at the time of filing would be motivated with a reasonable expectation of success to direct such a treatment method to such a subject that further requires reducing insulin resistance because 1) Yang 2008 discloses that SYK inhibition inhibits activation of NF-κB through the high glucose-induced tyrosine phosphorylation of IκBα route, and 2) as Dandona 2004 explains, activation of NF-κB leads to the activation of inflammatory cytokines, the subsequent inhibition of insulin signaling, and the rise of insulin resistance.
Therefore, claim 6 was obvious at the time of filing.
Claim 7 is Obvious over Arthur 2013 in view of van Eeuwijk 2016, Kurniawan 2020 and Ma 2016
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Arthur 2013 in view of van Eeuwijk 2016, Kurniawan, Dhadhang Wahyu, et al., "Role of spleen tyrosine kinase in liver diseases", World Journal of Gastroenterology, vol. 26, no. 10, pp. 1005-1019 (2020), hereinafter “Kurniawan 2020”, and Ma, Terry King-Wing, et al., "Spleen tyrosine kinase: a crucial player and potential therapeutic target in renal disease", Nephron vol. 133, no. 4, pp. 261-269 (2016), hereinafter “Ma 2016”.
Arthur 2013 and van Eeuwijk 2016 are relied upon as above.
Regarding claim 7, it depends upon claim 1 and recites that the subject requires reducing liver and kidney damage.
Arthur 2013 and van Eeuwijk 2016 do not expressly teach that administration of SYK inhibitors may reduce liver and kidney damage in a subject with diabetes.
However, one having ordinary skill in the art at the time of filing would have a reasonable expectation of success in treating diabetes by administering a SYK inhibitor to a subject that requires reducing liver and kidney damages because SYK inhibition is known to impart anti-inflammatory properties that prevent and reduce liver (Kurniawan 2020) and kidney (Ma 2016) damage.
Kurniawan 2020
Kurniawan 2020 generally discloses SYK as a therapeutic target in liver disease. See, e.g., Kurniawan 2020 at Abstract:
In liver, SYK expression has been observed in parenchymal (hepatocytes) and non-parenchymal cells (hepatic stellate cells and Kupffer cells), and found to be positively correlated with the disease severity. The implication of SYK pathway has been reported in different liver diseases including liver fibrosis, viral hepatitis, alcoholic liver disease, non-alcoholic steatohepatitis and hepatocellular carcinoma. Antagonism of SYK pathway using kinase inhibitors have shown to attenuate the progression of liver diseases thereby suggesting SYK as a highly promising therapeutic target.
Kurniawan 2020 at Abstract.
Kurniawan 2020 further summarizes results from SYK inhibition in various models of liver disease in Table 2, reproduced below:
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Kurniawan 2020 at 1014.
Ma 2016
Ma 2016 generally discloses SYK as a therapeutic target in renal disease. See, e.g., Ma 2016 at 263, Table 1, which is reproduced below on the following page (summarizing results from SYK inhibition in animal models of renal disease).
In particular, SYK inhibition has been shown to prevent and reduce renal injury in models of glomerulonephritis, Ma 2016 at 263-266, and in other models of renal diseases including acute renal allograft nephropathy, post-transplant lymphoproliferative disease, renal fibrosis and possibly diabetic nephropathy, Ma 2016 at 266.
Further, with respect to diabetic nephropathy, Ma 2016 discloses that:
Previous in vitro studies showed that Syk was involved in high-glucose-induced activation of nuclear factor (NF)-κB in human glomerular endothelial cells [42] and proximal tubular cells [43]. NF-B activation plays an important role in the signaling pathway of fibrosis. Preliminary animal study also showed a beneficial role of Syk inhibitor in autoimmune diabetes [44] .
Ma 2016 at 266.
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Ma 2016 at 263, Table 1
Claim 7 was Obvious at the Time of Filing
One having ordinary skill in the art would have a reasonable expectation of success in treating diabetes in a subject with SYK inhibitor BI-1002494 for the reasons stated regarding the obviousness of claim 1. One having ordinary skill in the art at the time of filing would be motivated with a reasonable expectation of success to direct such a treatment method to such a subject that further requires reducing liver and kidney damages because Kurniawan 2020 and Ma 2016 teach that SYK is a therapeutic target in liver and kidney diseases, respectively, and that inhibition of SYK results in reduction and prevention of damages associated with such diseases.
Therefore, claim 7 was obvious at the time of filing.
Claim 8 is Obvious over Arthur 2013 in view of van Eeuwijk 2016 and Phua 2013
Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Arthur 2013, in view of van Eeuwijk 2016 and Phua, Eng-Joo, et al., "Cromolyn sodium for insulin-induced lipoatrophy: old drug, new use", Diabetes Care, vol. 36, no. 12, pp. e204-e205 (2013), hereinafter “Phua 2013”.
Arthur 2013 and van Eeuwijk 2016 are relied upon as above.
Regarding claim 8, it depends upon claim 1 and recites that the method further comprises administering cromolyn or a pharmaceutically acceptable salt thereof.
Arthur 2013 and van Eeuwijk 2016 do not disclose the use of cromolyn in subjects with diabetes.
However, one having ordinary skill in the art at the time of filing would have a reasonable expectation of success in treating diabetes with a method that further comprises administering cromolyn or a pharmaceutically acceptable salt thereof because subjects that receive insulin injections may develop local insulin-induced lipoatrophy at the site of insulin administration, which may be treated using topical application of cromolyn sodium (Phua 2013).
As background, subjects with diabetes often receive insulin administration typically through injection because 1) in subjects with Type 1 diabetes, the “pancreatic beta cells are destroyed and insulin secretion is absolutely lacking,” Specification at 2, and 2) in some cases of subjects with Type 2 diabetes, “blood sugar may also be controlled only with insulin injections.” Specification at 3.
Phua 2013
Phua 2013 generally discloses the use of cromolyn sodium for insulin-induced lipoatrophy. Phua 2013 defines local insulin-induced lipoatrophy as “an immune-mediated loss of subcutaneous adipose tissue at insulin administration sites, [which] is now a rare complication of insulin therapy in patients with diabetes.” Phua 2013 at e204.
Phua 2013 discloses that local insulin-induced lipoatrophy “poses a clinical challenge owing to erratic insulin absorption at affected areas and distressing cosmetic issues.” Id.
Regarding the use of cromolyn, Phua 2013 discloses the results from twenty-four therapeutic interventions for insulin-induced lipoatrophy, wherein diabetic patients saw complete resolution of local insulin-induced lipoatrophy by topical cromolyn sodium application. See, e.g., Phua 2013 at e204, Table 1, reproduced below.
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Phua 2013 at e204, Table 1.
Claim 8 was Obvious at the Time of Filing
One having ordinary skill in the art would have a reasonable expectation of success in treating diabetes in a subject with SYK inhibitor BI-1002494 for the reasons stated regarding the obviousness of claim 1. One having ordinary skill in the art at the time of filing would recognize that subjects with diabetes receiving insulin injections may develop local insulin-induced lipoatrophy from insulin administration, which “poses a clinical challenge owing to erratic insulin absorption at affected areas and distressing cosmetic issues.” Phua 2013 at e204. One having ordinary skill in the art at the time of filing would be motivated with a reasonable expectation of success to include administration of cromolyn in a method of treating diabetes in a subject because Phua 2013 discloses that topical application of cromolyn sodium may lead to complete resolution of local insulin-induced lipoatrophy.
Therefore, claim 8 was obvious at the time of filing.
Claims 9-12 are Obvious over Arthur 2013 and WO’128 in view of van Eeuwijk 2016
Claims 9-12 are rejected under 35 U.S.C. 103 as being unpatentable over Arthur 2013 and WO’128, in view of van Eeuwijk 2016.
Claims 9-10
Regarding claim 9, it recites a pharmaceutical composition for preventing or treating diabetic complications containing BI-1002494 or a pharmaceutically acceptable salt thereof as an active ingredient.
Claim 10 recites the pharmaceutical composition of claim 9, and specifies that the “diabetic complications” are one or more selected from the group consisting of diabetic retinopathy, diabetic stroke, diabetic cardiovascular disease, diabetic lung disease, diabetic peripheral neuropathy, diabetic wound healing delay, and diabetic cancer metastasis.
Arthur 2013 and van Eeuwijk 2016 are relied upon as above.
WO’128 discloses pharmaceutical compositions comprising compounds of the invention, such as BI-1002494. See supra discussion of WO’128 in the background section pertaining to the obviousness of claim 1.
Arthur 2013 discloses that SYK inhibitors may be used to provide significant protection from arterial thrombosis, which is a critical complication of diabetic cardiovascular disease. See supra discussion of Arthur 2013.
Arthur 2013 and WO’128 do not expressly teach that BI-1002494 may be used for preventing or treating diabetic complications such as diabetic cardiovascular disease.
However, one having ordinary skill in the art at the time of filing would have a reasonable expectation of success in preparing a pharmaceutical composition preventing or treating diabetic complications, such as diabetic cardiovascular disease, containing BI-1002494, because van Eeuwijk 2016 discloses that BI-1002494 was known to profoundly protect mice from arterial thrombosis.
van Eeuwijk 2016 discloses that BI-1002494 was known to profoundly protect mice from arterial thrombosis. See supra discussion of van Eeuwijk 2016.
One having ordinary skill in the art would have a reasonable expectation of success in preparing a pharmaceutical composition comprising BI-1002494 as the active ingredient because WO’128 discloses pharmaceutical compositions comprising compounds of the invention, such as BI-1002494. One having ordinary skill in the art at the time of filing would have a reasonable expectation of success in using such a pharmaceutical composition for preventing or treating diabetic complications because 1) Arthur 2013 discloses that SYK inhibitors may be used to provide significant protection from arterial thrombosis, which is a critical complication of diabetic cardiovascular disease, and 2) van Eeuwijk 2016 discloses that the SYK inhibitor BI-1002494 was known to profoundly protect mice from arterial thrombosis.
Therefore, claims 9 and 10 were obvious at the time of filing.
Claims 11-12
Regarding claim 11, is recites a pharmaceutical composition “for preventing or treating diabetes-related metabolic abnormalities” containing BI-1002494 or a pharmaceutically acceptable salt thereof as an active ingredient.
Claim 12 recites the pharmaceutical composition of claim 11, and specifies that the “diabetes-related metabolic abnormalities” are one or more selected from the group consisting of hyperglycemia, liver damage, kidney damage, pancreas damage, and blood lipid abnormalities.
Arthur 2013, WO’128, and van Eeuwijk 2016 are relied upon as above.
WO’128 discloses pharmaceutical compositions comprising compounds of the invention, such as BI-1002494. See supra discussion of WO’128 in the background section pertaining to the obviousness of claim 1.
Arthur 2013 discloses that GPVI-mediated ROS generation is exacerbated in poorly controlled diabetic monkeys (i.e., STZ induced diabetic monkeys receiving a reduced insulin regime). See supra discussion of the passage from Arthur 2013 at 3-4.
Arthur 2013 explains that ROS generation leads to platelet aggregation by involvement of SYK. See supra discussion of the passage from Arthur 2013 at 1-2.
Arthur 2013 discloses that inhibition of SYK with the SYK inhibitor BAY61-3606 reduced CRP-induced ROS generation. See supra discussion of the passage from Arthur 2013 at 4.
Arthur 2013 discloses that “Syk inhibition could prove to be an effective antiplatelet strategy for diabetic patients because of its minimal impact on primary haemostasis while providing significant protection from arterial thrombosis [40].” Arthur 2013 at 7.
Arthur 2013 discloses that its results “point to a potential antithrombotic therapeutic benefit of Syk inhibition in hyperglycaemic diabetes.” Arthur 2013 at Abstract.
Arthur 2013 discloses that SYK inhibitors may be used to provide significant protection from arterial thrombosis, which is a critical complication of diabetic cardiovascular disease. See supra discussion of Arthur 2013.
Arthur 2013 and WO’128 do not expressly teach that BI-1002494 may be used for preventing or treating diabetes-related metabolic abnormalities.
However, one having ordinary skill in the art at the time of filing would have a reasonable expectation of success in preparing a pharmaceutical composition for preventing or treating diabetes-related metabolic abnormalities, such as hyperglycemia, containing BI-1002494, because van Eeuwijk 2016 discloses that BI-1002494 was known to profoundly protect mice from arterial thrombosis.
van Eeuwijk 2016 discloses that BI-1002494 was known to profoundly protect mice from arterial thrombosis. See supra discussion of van Eeuwijk 2016.
One having ordinary skill in the art would have a reasonable expectation of success in preparing a pharmaceutical composition comprising BI-1002494 as the active ingredient because WO’128 discloses pharmaceutical compositions comprising compounds of the invention, such as BI-1002494. One having ordinary skill in the art at the time of filing would have a reasonable expectation of success in using such a pharmaceutical composition for preventing or treating diabetes-related metabolic abnormalities, such as hyperglycemia, because 1) Arthur 2013 discloses that “Syk inhibition could prove to be an effective antiplatelet strategy for diabetic patients because of its minimal impact on primary haemostasis while providing significant protection from arterial thrombosis”, Arthur 2013 at 7, and that its results “point to a potential antithrombotic therapeutic benefit of Syk inhibition in hyperglycaemic diabetes”, Arthur 2013 at Abstract, and 2) van Eeuwijk 2016 discloses that the SYK inhibitor BI-1002494 was known to profoundly protect mice from arterial thrombosis.
Therefore, claims 11 and 12 were obvious at the time of filing.
Prior art Cited but not Applied
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Electronic Supporting Information/Supplemental Material for van Eeuwijk 2016, available online at website for the Arteriosclerosis, Thrombosis, and Vascular Biology journal and attached hereto.
Provides the structure of BI-1002494. See supra footnote regarding van Eeuwijk 2016.
Lamb DJ, Wollin SL, Schnapp A, et al., “Bi 1002494, a novel potent and selective oral syk inhibitor displays differential potency in human basophils and b-cells”, J. Pharmacol. Exp. Ther., vo. 357, no. 3, pp. 554-561 (2016) (Lamb 2016).
Provides the structure of BI-1002494. See supra footnote regarding van Eeuwijk 2016.
Tabeling, C., et al., “Spleen tyrosine kinase inhibition blocks airway constriction and protects from Th2-induced airway inflammation and remodeling”, Allergy, vol. 72, no. 7, pp. 1061-1072 (2017) (Tabeling 2017).
Provides a study of BAY 61-3606 and BI-1002494 in models of asthma.
Conclusion
No claims are allowed.
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/C.E.R./ Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/ Supervisory Patent Examiner, Art Unit 1629
1 The examiner notes that the structure applicant provides for (R)-4-{(R)-1-[7-(3,4,5-trimethoxy-phenyl)-[1,6] naphthyridine-5-yloxy]-ethyl}pyrrolidine-2-one fails to indicate both chiral sites that the chemical name requires. Further, the examiner assumes that there is an implicit hydrogen on the nitrogen of the pyrrolidine-2-one ring that the chemical name requires.
2 The examiner assumes that there is an implicit hydrogen on the nitrogen of the pyrrolidine-2-one ring that the chemical name requires.
3 WO’128 is the publication of International Application No. PCT/EP2011/050871, which was filed on January 21, 2011.
4 For clarity, WO’128 does not use the pharmaceutical compound number BI-1002494 to refer to the example 35 compound. The BI-1002494 nomenclature, however, was known prior to the effective filing date of the instant application. See infra footnote regarding van Eeuwijk 2016.
5 R788 is also known as fostamatinib.
6 van Eeuwijk 2016 uses the pharmaceutical compound number BI-1002494 without the hyphen, and in areas of the text, the BI prefix appears as “B1” or “Bl”. However, the supporting information for van Eeuwijk 2016 provides the structure for the compound of the study, wherein it references “Lamb DJ, Wollin SL, Schnapp A, et al. Bi 1002494, a novel potent and selective oral syk inhibitor displays differential potency in human basophils and b-cells. J. Pharmacol. Exp. Ther. 2016,” to provide the structure of BI 1002494. The 2016 Lamb article is attached hereto, and provides the structure of BI 1002494 in Fig. 1.