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 with traverse of species of vascular cognitive impairment, SEQ ID NO: 1 modified with M-SPA-10K in the reply filed on 08/31/2016 is acknowledged. The traversal is on the ground(s) that the claims have been amended to require mutation of one of N141, F142 or S143. This is not found persuasive because as far as at least claim 3 is suggested by the prior art for the reasons set forth in the rejections under 35 U.S.C. 103 below, the claims do not recite a special technical feature even after amendment.
The requirement is still deemed proper and is therefore made FINAL.
Claim Objections
Claim 16 is objected to because of the following informalities:
Claim 16 recites four structural formulas. The conjunction “and” should appear between the last two formulas.
The last two formulas state “wherein m is” when the formula appear to contain “n” as the only variable. Since only one variable appears in the formulas, this is understood as a typographical error and a rejection under 35 U.S.C. 112(b) is not made; however, correction is required.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 3 and 13-16 (all pending claims) 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 3 recites the limitation "the subject" in line 2. There is insufficient antecedent basis for this limitation in the claim. There is no literal antecedent basis for “the subject” as recited and further no claim term that provides a reasonable inherent antecedent basis for “the subject.” As such, an ordinarily skilled artisan cannot understand how to avoid infringement of the claim.
Claim 3 recites the limitation "the wild-type human kallikrein I" in line 8. There is insufficient antecedent basis for this limitation in the claim. There is no literal antecedent basis for “the wild-type human kallikrein I” as recited and further no claim term that provides a reasonable inherent antecedent basis for “the wild-type human kallikrein I.” Further, “the wild-type human kallikrein I” cannot be assumed to be associated with a specific amino acid sequence, such as SEQ ID NO: 5 provided in the specification.
Claim 3 recites the limitation "in the amino acid sequence N141-F142-S143 of the wild-type human kallikrein I" in line 9. There is insufficient antecedent basis for this limitation in the claim. There is no explicit antecedent basis for “the” amino acid sequence of wild-type human kallikrein I as to provide an explicit nor inherent antecedent basis for a specific sequence N141-F142-S143. That is, the claim limitation is not just the sequence NFS that can provide a self-antecedent basis, but rather a specific sequence associated with positions 141, 142 and 143 wherein there is no antecedent basis for positional numbering in the claim. As such, an ordinarily skilled artisan cannot recognize if an embodiment has a mutation in the sequence N141-F142-S143 as to avoid infringement. A specific Sequence Identifier can be recited in order to define the meaning of the amino acid sequence N141-F142-S143 of the wild-type human kallikrein I.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 3 and 13-16 (all pending claims) 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 treatment of post-stroke cognitive impairment and small vessel disease, does not reasonably provide enablement for treatment of vascular cognitive impairment (that is caused by causes other than stroke) and Alzheimer's disease (AD) with vascular lesions. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
An “analysis of whether a particular claim is supported by the disclosure in an application requires a determination of whether that disclosure, when filed, contained sufficient information regarding the subject matter of the claims as to enable one skilled in the pertinent art to make and use the claimed invention.” MPEP 2164.01. “A conclusion of lack of enablement means that . . . the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention [i.e. commensurate scope] without undue experimentation.” In re Wright, 999 F.2d 1557,1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993); MPEP 2164.01.
In In re Wands, 858 F.2d 731, 8 USPQ2d 1400 (Fed. Cir. 1988), several factors implicated in determination of whether a disclosure satisfies the enablement requirement and whether any necessary experimentation is “undue” are identified. These factors include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988). No single factor is independently determinative of enablement; rather “[i]t is improper to conclude that a disclosure is not enabling based on an analysis of only one of the above factors while ignoring one or more of the others.” MPEP 2164.01. Likewise, all factors may not be relevant to the enablement analysis of any individual claim.
“According to In re Bowen, 492 F.2d 859, 862-63, 181 USPQ 48, 51 (CCPA 1974), the minimal requirement is for the examiner to give reasons explaining the uncertainty of the enablement. This standard is applicable even when there is no evidence in the record of operability without undue experimentation beyond the disclosed embodiments.” See also In re Brana, 51 F.3d 1560, 1566, 34 USPQ2d 1436, 1441 (Fed. Cir. 1995); MPEP 2164.04.
Factors (A)-(C)
Claim sets forth a method of treating or ameliorating a disease or disorder being vascular cognitive impairment, post-stroke cognitive impairment, Alzheimer’s disease with vascular lesions, cerebral small vessel disease, or cognitive dysfunction due to cerebral small vascular disease by administering to an appropriate subject a human kallikrein I mutant as recited (herein, “KLK1” will refer to the recited mutant throughout this Office Action unless indicated otherwise.)
The following is noted about the nature of the invention and state of prior art.
--Alexander-Curtis et al. (Human tissue kallikrein in the treatment of acute ischemic stroke, Therapeutic Adv. Neurological Disorders, 12, 2019, 1-15), abstract, sets forth:
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--Mella et al. (Involvement of kallikrein-related peptidases in nervous system disorders, Frontiers Cellular Neuroscience 14, 2020 166), page 4 (left col.) states: “Nevertheless, it has recently been
reported that KLK6 levels in cerebrospinal fluid (CSF) are significantly increased in patients with Alzheimer’s disease and elevated CSF phosphorylated tau (p-Tau), but not in Alzheimer’s disease patients with normal CSF p-Tau levels. This observation may indicate that KLK6 is associated with Tau pathology and has the potential to be a suitable biomarker in tau pathology Alzheimer’s disease-related.” KLK6 is a different protein from KLK1. Identification of KLK6 is a biomarker for certain pathologies of Alzheimer’s disease is not a indication that KLK6 an be administered to treat any form of Alzheimer’s disease.
--Chojkak-Lukasiewicz et al. (Cerebral small vessel disease, Adv Clin Exp Med 30, 2021, 349-56), abstract, states: “Cerebral small vessel disease (CSVD) is the most common, chronic and progressive vascular disease. The changes affect arterioles, capillaries and small veins supplying the white matter and deep structures of the brain. It is the most common incidental finding on brain scans, especially in people over 80 years of age. The disease is characterized by a diverse clinical and radiological picture. It is primarily responsible for stroke incidents, gait disturbances, depression, cognitive impairment [i.e. dysfunction], and dementia in the elderly. . . . There is no causal treatment and management is mainly based on combating known risk factors for cardiovascular disease (CVD).”
--Singh et al. (The contact activation system and vascular factors as alternative targets for Alzheimer's disease therapy, Res Pract Thromb Haemost 5, 2021, e12504), abstract: states: “Alzheimer's disease (AD) is the most common neurodegenerative disease, affecting millions of people worldwide. Extracellular beta- amyloid (Aβ) plaques and neurofi brillary tau tangles are classical hallmarks of AD pathology and thus are the prime targets for AD therapeutics. However, approaches to slow or stop AD progression and dementia by reducing Aβ production, neutralizing toxic Aβ aggregates, or inhibiting tau aggregation have been largely unsuccessful in clinical trials.” Singh, page 3, left col., states:
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As such, Singh indicates that kallikrein that increases bradykinin (which is understood to be KLKI) is detrimental to those with Alzheimer’s disease by being inflammatory. See Singh, Fig. 1. Kaplan et al. (Alzheimer’s Disease, Cells 13, 2024, 2039) further, abstract, indicates “The aggregation of Aβ 1-38, 1-40, and 1-42 is optimal after incubation for 3 days, 3 h, and under 1 min, respectively. The cascade is
initiated by the autoactivation of factor XII upon binding to aggregated Aβ; then, prekallikrein is
converted to kallikrein, which cleaves high-molecular-weight kininogen (HK) to release bradykinin” and “Given the current state of therapy for Alzheimer’s disease, which includes monoclonal antibodies that retard the rate of progression by 30% at most and have significant side effects, it seems imperative to explore prophylaxis using one of the long-acting agents that target plasma kallikrein or factor XIIa. There is a long-acting bradykinin antagonist in development, and techniques to target kallikrein mRNA to lower levels or knock out the prekallikrein gene are being developed.”
Kaplan is not prior art but is a review article that evidences the state of the art at time of filing. Sing and Kaplan both indicate that kallikrein activity is detrimental to AD (whether with vascular lesions or not) wherein Kaplan suggests knocking out of kallikrein gene as a treatment for AD.
--Dichgans (Vascular cognitive impairment, Circulation Res., 2017, 573) teaches “Vascular cognitive impairment refers to all forms of cognitive disorder associated with cerebrovascular disease, regardless of the specific mechanisms involved. It encompasses the full range of cognitive deficits from mild cognitive impairment to dementia. In principle, any of the multiple causes of clinical stroke can cause vascular cognitive impairment. Recent work further highlights a role of microinfarcts, microhemorrhages, strategic white matter tracts, loss of microstructural tissue integrity, and secondary neurodegeneration.” In principle, any of the multiple etiologies of stroke (small vessel disease [SVD], large-artery atherosclerosis, cardioembolism, or other less common etiologies of stroke) can cause VCI.” Dichgans, page 575, left col.
Factors (D)-(E)
The ordinary skill in the art is high as represented by a medical physician. Regardless, as reviewed above, KLK1 is taught in the prior to be beneficial for treating neurologic impairment following ischemic stroke. Singh and Kaplan, as discussed, indicated that KLK1 that affects bradykinin production aggravates AD and is not expected to treat AD symptoms. Dichgans teaches that vascular cognitive impairment has diverse causes including small vessel disease and large-artery atherosclerosis.
It is unpredictable that KLK1 treats any conditions other than neurologic impairment following ischemic stroke wherein vascular cognitive impairment (from all potential causes) and AD with or without vascular legions and cerebral small vessel disease with or without cognitive dysfunction/impairment are caused by distinct etiologies that are different from ischemic stroke. Again, it is noted that Singh and Kaplan indicate that KLK1 is detrimental to AD. Example 4 of the specification shows treatment with KLK1 with a BCAS model of small vessel, which is understood as a model of small vessel disease which reports a significant improvement upon treatment with KLK1.
That is, although the record is convincing regarding the effectiveness of KLK1 and mutants as recited to treat ischemic stroke and, through a presented animal model, small vessel disease, the same result cannot be reasonably predicted to extend to treatment of any of vascular cognitive impairment (that is caused by causes other than stroke) and Alzheimer's disease with vascular lesions that have other mechanisms for causing cognitive impairment and other symptoms such that treatment of any of these conditions with KLK1 as recited is unpredictable.
Factors (H)
In the absence of any evidence in the prior art nor the specification that KLK1 or mutants thereof have any affect to ameliorate diseases selected from vascular cognitive impairment (that is caused by causes other than stroke) and Alzheimer's disease with vascular lesions, an ordinarily skilled artisan would have to engage in unguided experimentation in order to treat any of vascular cognitive impairment (that is caused by causes other than stroke) and Alzheimer's disease with vascular lesions. Such unguided experimentation is not routine in the art as is therefore undue.
As such, all of the Wands factors reviewed above weight towards non-enablement of treatment of vascular cognitive impairment (that is caused by causes other than stroke) and Alzheimer's disease with vascular lesions by administration of KLK1 as recited.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 3 and 13-16 is/are rejected under 35 U.S.C. 103 as being obvious over Ma et al. (U.S. 2025/0011747 A1) (filed 11/16/2022 and claiming priority to CN 202111353294.2 filed 11/16/2021) further in view of Tatemichi et al. (Cognitive impairment after stroke, J. Neurology, Neurosurgery Psychiatry 57, 1994, 202-207) (previously cited). CN116135973A is cited as a copy of CN 202111353294.2 with an English language machine translation.
The applied reference has a common assignee/inventor with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2).
Ma, abstract, states:
Provided are low glycosylated kallikrein I with no or a small amount of glycosylation at the NFS sequence and polyethylene glycol modified product and pharmaceutical applications. KLK1 with lower glycosylation at NFS is more active than KLK1 with higher glycosylation at NFS. A recombinant KLK1 mutant without N-glycosylation at the NFS sequence is also provided, containing only two N-glycosylation sites at NMS and NHT. Glycosylation of the recombinant KLK1 mutant is relatively more consistent, the molecular weight of the product is relatively more homogeneous, the yield is higher, the purification process is simpler, and the biological activity is higher, and the quality is more controllable.
Preferably, F(phenylalanine) at NFS of KLK1 is mutated to proline, that is, phenylalanine at position 142 is mutated to proline, and 0, 1, or 2 amino acids of N and S at NFS are mutated to any other amino acid, so that the variant does not constitute N-glycosylation motif at the corresponding position. Thus, there is no glycosylation at position 141. Similarly, in addition to obtain more homogeneous and higher yield of low glycosylated KLK1, the mutants have better activity than unmutated low glycosylated KLK1. Ma, para. [0018].
As preferred, amino acid sequence of the KLK1 mutant is shown as SEQ ID No: 3, SEQ ID No: 4, SEQ ID No: 5, or SEQ ID No: 6. Ma, para. [0022].
An alignment between SEQ ID NO: 5 of the specification and SEQ ID NO: 4 of Ma is as follows, wherein SEQ ID NO: 5 of the specification is understood as a wild-type human kallikrein I:
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As can be seen in the alignment above, SEQ ID NO: 4 of Ma has a substitution N141D relative to SEQ ID NO: 5 of the specification in the sequence N141-F142-S143 wherein Aspartate (D) is an acidic amino acid. SEQ ID NO: 4 of Ma is identical to recited SEQ ID NO: 2.
“The present invention provides pegylated KLK1 that significantly improves protein stability, reduces immunogenicity, improves in vivo pharmacokinetic properties of the protein, and retains protein activity.” Ma, para. [0026].
“Preferably, the PEG modifier is linear PEG succinimidyl propionate with molecular weight of 5 kDa-10 kDa, and the general formula is shown in (2),
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where n is an integer from 105 to 225.” Ma, para. [0030].
The cited pegylation formula in para. [0030] of Ma meets the first formula shown in claim 16 when n is 105.
As such, Ma teaches a recombinant human kallikrein I (KLK1) mutant comprising a N141D mutation relative to wild-type human KLK1 with N141 mutated and zero (0) of residues F132 and S143 mutated that is identical to recited SEQ ID NO: 2. Ma further teaches that any such mutant KLK1 can be a peglylated kallikrein 1 as directly recited in claims 15 and 16.
“Those skilled in the art can reasonably expect that the recombinant KLK1 mutants and their compositions have the same function as native KLK1 and can be used in the treatment, prevention, prognosis recovery, and prevention of recurrence of acute ischemic stroke, peripheral neuropathy, retinopathy, fundus disease, hypertension, diabetic nephropathy, IgA nephritis, and chronic kidney disease.” Ma, para. [0024].
“SD rats, male, SPF grade, weighing 270-300 g. The cerebral ischemia-reperfusion model of middle cerebral artery occlusion (MCAO) [i.e. stroke] was prepared by using the intraluminal suture method in rats.” Ma, para. [0187]. “Grouping: There were four groups, namely sham operation group, model group, and pancreatic kallikrein I group for injection (0.41 U/kg, intramuscular injection, pancreatic kallikrein I for injection was PEG10K-modified Kb, the preparation method was as described in Example 5, in which Kb was KLK1 extracted from pig pancreas). Urinary kallikrein group (0.1IU/kg, intravenous injection). In the administration group, the drug was administered 2 h after reperfusion. The specific activity of the samples in all animal experiments was calculated according to method 1 of Example 6.” Ma, para. [0188].
“In combination with examples 13 and 14, PEG10K-hKLK1X1 by intravenous injection (0.1IU/kg) and intramuscular injection (0.41 U/kg) all had a very significant brain protection effect, and can effectively treat the neurological defect symptoms and improve the cerebral infarction area in animals after stroke.” Ma, para. [0218]. This is understood as a description of treatment with an effective amount of the KLK1 derivative.
Treatment of neurological defect symptoms in an animal model after stroke is understood to be within the scope of treating post-stroke cognitive impairment (i.e. neurological defect symptoms). "The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious." Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985); MPEP 2145(II). Here, Ma explicitly teach administration of KLK1 variants as discussed to animals/subjects after stroke to improve neurological defect symptoms and improve the cerebral infarction. A recognition that cognitive impairment is specifically treated/improved is recognition of another advantage which would flow naturally from following the suggestion of the prior art. Further, while Ma in working examples teach an animal model of stroke, Ma is directed towards the expectation that KLK1 variants will be applied to human patients due to discussion of human KLK1. See Ma, para. [0015]. Further, impairment of cognitive function following ischemic stroke is common. See Tatemichi, abstract (Cognitive function was examined in 227 patients three months after admission to hospital for ischaemic stroke, and in 240 stroke-free controls, using 17 scored items that assessed memory, orientation, verbal skills, visuospatial ability, abstract reasoning, and attentional skills.) As such, as far as Ma teaches the administration of recombinant kallikrein I variants to subjects following ischemic stroke with an expectation in improvement of neurological outcomes, any observation that the described improvement in neurological outcomes includes ameliorating cognitive impairment (post-stroke cognitive impairment) is “recogni[tion] another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious.” MPEP 2145(II). While working examples of Ma reference animal models, treatment of stroke by administering recombinant human KLK1 variants as discussed is understood to be applicable to human subjects wherein improvement of cognitive abilities is relevant and desirable.
The provided translation of CN 116135973 A indicates that the disclosure of CN 202111353294.2 is substantially identical to Ma.
This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
Claim(s) 3 and 13 is/are rejected under 35 U.S.C. 103 as being unpatentable over Charles (U.S. 2013/0323222 A1) further in view of Tang et al. (Expression, Crystallization, and Three-dimensional Structure of the Catalytic Domain of Human Plasma Kallikrein, J. Biol. Chem. 280, 2005, 41077-89), Alexander-Curtis et al. (Human tissue kallikrein in the treatment of acute ischemic stroke, Therapeutic Adv. Neurological Disorders 12, 2012, 1-15) (previously cited) and Tatemichi et al. (Cognitive impairment after stroke, J. Neurology, Neurosurgery Psychiatry 57, 1994, 202-207) (previously cited).
Charles, abstract, states:
Provided are preparations of tissue kallikrein-1 (KLK1) glycoforms having a defined number of oligosaccharide units per KLK1 molecule. Also provided are mixtures of such glycoforms, pharmaceutical compositions containing such glycoforms or mixtures thereof, methods of obtaining the rhKLK1 glycoforms, and therapeutic uses thereof.
“In some embodiments, the subject has an ischemic condition. Non-limiting examples include cardiac ischemia (myocardial ischemia), ischemic colitis, brain ischemia (ischemic stroke), limb ischemia, and cutaneous ischemia. These and related medical conditions can be diagnosed according to routine techniques in the art.” Charles, para. [0113].
“In some aspects of a composition of the present invention, one or more of said glycans are N-linked glycans. In some aspects, one or more of the glycans are attached at amino acid residues 78, 84, or 141 of KLK1 as defined by SEQ ID NO:1. In some aspects, the three glycans of the first KLK1 polypeptide are N-linked glycans at residues 78, 84, and 141. In some aspects, the two glycans of the second KLK1 polypeptide are N-linked glycans at residues 78 and 84 but not 141. In some aspects, the ratio of first KLK1 polypeptide and the second KLK1 polypeptide in the composition is about 50:50.” Charles, para. [0006].
“A “variant” of a starting or reference polypeptide is a polypeptide that has an amino acid sequence different from that of the starting or reference polypeptide. Such variants include, for example, deletions from, insertions into, and/or substitutions of residues within the amino acid sequence of the polypeptide of interest. A variant amino acid, in this context, refers to an amino acid different from the amino acid at the corresponding position in a starting or reference polypeptide sequence. Any combination of deletion, insertion, and substitution may be made to arrive at the final variant or mutant construct, provided that the final construct possesses the desired functional characteristics. The amino acid changes also may alter post-translational processes of the polypeptide, such as changing the number or position of glycosylation sites.” Charles, para. [0047].
SEQ ID NO: 1 of Charles (Db) comprises a sequence over 99% identical to SEQ ID NO: 5 of the specification as follows:
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It is noted that the first 24 amino acid residues of SEQ ID NO: 1 of Charles are numbered negative such that positions 78, 84 and 141 of SEQ ID NO: 1 of Charles align with SEQ ID NO: 5 of the specification.
Charles teaches “In some aspects, the two glycans of the second KLK1 polypeptide are N-linked glycans at residues 78 and 84 but not 141” and discusses “The amino acid changes also may alter post-translational processes of the polypeptide, such as changing the number or position of glycosylation sites.” Charles does not explicitly teach substitution of N141 with another amino acid residue in order to generate “KLK1 polypeptide are N-linked glycans at residues 78 and 84 but not 141.” However, Tang teaches that it is known in the prior art to mutate a Asn amino acid residue of kallikrein to produce a deglycosylated form.
“FIG. 1 is an SDS-PAGE gel stained with Coomassie Blue stain of various amounts of recombinant human KLK1 purified from CHO or 293 cell lines following transient transfection.” Charles, para. [0028]. As such, the KLK1 polypeptides described by Charles are understood a recombinant human kallikrein I polypeptides.
Tang, abstract, states: “Plasma kallikrein is a serine protease that has many important functions, including modulation of blood pressure, complement activation, and mediation and maintenance of inflammatory responses.” “Sequences encoding the glycosylation asparagines, Asn377, Asn434, and Asn475, and the cysteines, Cys364 and Cys484, were mutated to encode Glu377, Glu434, Glu475, Ser364, and Ser484, respectively, through site-directed mutagenesis” to produce deglycosylated forms of kallikrein. Tang, page 41079, left col. The plasma kallikrein discussed in Tang is different from KLK1 that is understood to be a tissue kallikrein.
Again, Charles does not explicitly teach substitution of N141 with another amino acid residue in order to generate “KLK1 polypeptide are N-linked glycans at residues 78 and 84 but not 141.” However, in view of the teachings of Tang and further teachings in Charles that “The amino acid changes also may alter post-translational processes of the polypeptide, such as changing the number or position of glycosylation sites,” an ordinarily skilled artisan at time of filing would have been motivated to produce “KLK1 polypeptide are N-linked glycans at residues 78 and 84 but not 141,” by mutagenesis of N141 to a different amino acid, such as Glu (an acidic amino acid residue), in order to produce a form of KLK1 that is not glycosylated at amino acid residue 141. An ordinarily skilled artisan at time of filing would have been motivated to do this in order to predictably produce “KLK1 polypeptide are N-linked glycans at residues 78 and 84 but not 141.”
That is, Charles, with reference to claim 7 thereof, teaches a composition having a triple glycosylated isoform of KLK1 and a double glycosylated isoform of KLK1 (i.e. not glycosylated at position 141). Charles, para. [0082], teaches: “In certain embodiments, the glycoforms may be isolated by reverse phase HPLC. In another embodiment, the glycoforms may be isolated by size exclusion chromatography may be employed. . . . Once separated, the glycoforms can be recombined to generate the desired ratio.”
As such, Charles teaches that the composition with a triple glycosylated isoform of KLK1 and a double glycosylated isoform of KLK1 can be formed by isolating each isoform and combining as appropriate. Since the prior art, as discussed, suggests that residue N141 of KLK1 can be substituted, for example to Asp (acid residue), to block glycosylation at that position, an ordinarily skilled artisan at time of filing would have been motivated to do the same substitution to the KLK1 of SEQ ID NO: 1 of Charles in order to generate a separate double glycosylated isoform of KLK1 that can be combined in an appropriate ratio with the triple glycosylated isoform of KLK1 as discussed.
Regarding administering a recombinant KLK1 mutant with substitution at position N141 in an effective amount to treat post-stroke cognitive impairment in a subject in need thereof, “The present invention includes methods of treating a subject in need thereof, including administering to the subject a composition as described herein.” Charles, para. [0020]. “In some embodiments, the subject has an ischemic condition. Non-limiting examples include . . . brain ischemia (ischemic stroke).” Charles, para. [0113].
The use of KLK1 to treat strokes and neurological symptoms resulting therefrom is well-established in the prior art.
Alexander-Curtis, abstract, states:
Acute ischemic stroke (AIS) remains a major cause of death and disability
throughout the world. The most severe form of stroke results from large vessel occlusion
of the major branches of the Circle of Willis. The treatment strategies currently available in
western countries for large vessel occlusion involve rapid restoration of blood flow through
removal of the offending blood clot using mechanical or pharmacological means (e.g. tissue
plasma activator; tPA). This review assesses prospects for a novel pharmacological approach
to enhance the availability of the natural enzyme tissue kallikrein (KLK1), an important
regulator of local blood flow. KLK1 is responsible for the generation of kinins (bradykinin and
kallidin), which promote local vasodilation and long-term vascularization. Moreover, KLK1 has
been used clinically as a direct treatment for multiple diseases associated with impaired local
blood flow including AIS. A form of human KLK1 isolated from human urine is approved in the
People’s Republic of China for subacute treatment of AIS. Here we review the rationale for
using KLK1 as an additional pharmacological treatment for AIS by providing the biochemical
mechanism as well as the human clinical data that support this approach
“[T]he treatment period for all studies lasted between 7 and 21 days. The analysis showed that uKLK1 treatment was significantly associated with an improvement in neurological outcomes and a reduction in death and dependency at the 3-month follow up in the two well-controlled trials.” Alexander-Curtis, page 7, right col. Impairment of cognitive function following ischemic stroke is common known neurological symptom. See Tatemichi, abstract (Cognitive function was examined in 227 patients three months after admission to hospital for ischaemic stroke, and in 240 stroke-free controls, using 17 scored items that assessed memory, orientation, verbal skills, visuospatial ability, abstract reasoning, and attentional skills.) As such, as far as Alexander-Curtis teaches the administration of kallikrein I to subjects following ischemic stroke with an expectation in improvement of neurological outcomes, any observation that the described improvement in neurological outcomes includes ameliorating cognitive impairment (post-stroke cognitive impairment) is “recogni[tion] another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious.” MPEP 2145(II). While cited references including Charles reference animal models in the working examples, the taught treatments are understood to be applicable to treatment of human subjects wherein improvement of cognitive ability following stroke is relevant and desirable.
As such, wherein Charles teaches “In some embodiments, the subject has an ischemic condition. Non-limiting examples include . . . brain ischemia (ischemic stroke),” an ordinarily skilled artisan at time of filing would have been motivated to administer the recombinant KLK1 mutant suggested by Charles in view of Tang in the same manner as taught by Alexander-Curtis in order to treat and improve neurological outcomes in ischemic stroke that includes improvement of post-stroke cognitive impairment as discussed.
It is noted that administering a kallikrein I mutant with a mutation at N141 includes administering such mutant in combination with a wild-type KLK1 (e.g. a triple glycosylated isoform of KLK1) since the claims recite the open transitional phrase “comprising.”
An ordinarily skilled artisan at time of filing would readily understand that any recombinant KLK1 mutant administered should be done in an amount that results in a neurological and/or cognitive improvement that would constitute administering to the subject an effective amount of the recombinant KLK1 mutant.
In addition to the above, claim 3 recites “administering . . . recombinant kallikrein I mutant or a derivative thereof.” Such a “derivative” does not necessarily require a substitution to one of N141, F142 or S143, since claim 3 states that the “recombinant human kallikrein I mutant” has such a substitution but not necessarily a “derivative thereof.” As such, the recombinant KLK1 having SEQ ID NO: 1 of Charles without any further modification is a “derivative” of a recombinant kallikrein I mutant as recited.”
Claim(s) 3 and 13-16 (all pending claims) is/are rejected under 35 U.S.C. 103 as being unpatentable over Charles (U.S. 2013/0323222 A1), Tang et al. (Expression, Crystallization, and Three-dimensional Structure of the Catalytic Domain of Human Plasma Kallikrein, J. Biol. Chem. 280, 2005, 41077-89), Alexander-Curtis et al. (Human tissue kallikrein in the treatment of acute ischemic stroke, Therapeutic Adv. Neurological Disorders 12, 2012, 1-15) (previously cited) and Tatemichi et al. (Cognitive impairment after stroke, J. Neurology, Neurosurgery Psychiatry 57, 1994, 202-207) (previously cited) as applied to claims 3 and 13 above, and further in view of Ma et al. (U.S. 2017/0049864 A1).
Regarding claim 14, Charles and Tang, as discussed, do not directly suggest a KLK1 mutant identical to recited SEQ ID NO: 2.
First, SEQ ID NO: 1 of Charles has a substitution Q145E relative to recited SEQ ID NO: 2 and SEQ ID NO: 5 of the specification. There appears to be several sequence variations of human KLK1 known in the art including SEQ ID NO: 2 of Charles.
Ma, abstract, teaches:
The present invention relates to polyethylene glycol (PEG) modified protein drugs, and a PEGylated tissue kallikrein, a preparation method and use thereof are disclosed. The tissue kallikrein has a sequence as shown in SEQ ID No. 1 or SEQ ID No. 2, and the tissue kallikrein may be natural or recombinant. The PEG has a molecular weight of 20 to 40 kDa, and is conjugated to the N-terminal primary amino of the tissue kallikrein. In addition to the advantages of significantly extended half-life, significantly reduced immunogenicity and stable and uniform structure, the biological activity of the PEGylated KLK1 provided in the present invention is improved to a higher extent, which is more significant in the treatment of cerebral apoplexy and diabetic nephropathy in particular.
SEQ ID NO: 2 of Ma is identical to recited SEQ ID NO: 2 except for mutation at position 141 to Asp(D).
“Technical problems to be solved: the present invention provides a PEGylated tissue kallikrein (KLK1) having a high biological activity, a long half-life, and a low immunogenicity, and use thereof in the preparation of drugs for treating mild to moderate acute thrombotic cerebral infarction.” Ma, para. [0007]. Cerebral apoplexy is understood as a synonym for a stroke. That is, apoplexy means sudden bleeding/hemorrhage which in the context of “cerebral” is an ischemic stroke. Similarly, cerebral infarction is understood as a synonym for ischemic stroke.
“In FIG. 10, lane 1 is a recombinant hK1 protein with a greater relative molecular weight, lane 2 is a recombinant hK1 protein with a lower relative molecular weight, and lane 3 is a prestained protein loading Marker with a molecular weight ranging from 10 to 250 KD. The physicochemical properties and biological activity of the two recombinant hK1 proteins with different molecular weights have no difference, except that the glycosylation modifications are different.” Ma, para. [0053]. This description is suggestive of two glycoforms as discussed in Charles. Regardless, SEQ ID NO: 1 of Charles and SEQ ID NO: 2 of Ma are identical except for a single amino acid at position 145.
Substitution of known elements is obvious upon a finding of:
(1) a finding that the prior art contained a device (method, product, etc.) which differed from the claimed device by the substitution of some components (step, element, etc.) with other components;
(2) a finding that the substituted components and their functions were known in the art;
(3) a finding that one of ordinary skill in the art could have substituted one known element for another, and the results of the substitution would have been predictable; and
(4) whatever additional findings based on the Graham factual inquiries may be necessary, in view of the facts of the case under consideration, to explain a conclusion of obviousness. (MPEP 2143(I)(B)).
Here, (1) Charles teaches an isoform of KLK1 suggested for use for pharmaceutical purposes including treatment of stroke. (2) Ma teaches a KLK1 isoform (SEQ ID NO: 2 of Ma) that is identical to the KLK1 of Charles except for a single amino acid substitution. (3) An ordinarily skilled artisan at time of filing could have substituted the KLK1 of SEQ ID NO: 2 of Ma in replacement for the KLK1 in Charles. (4) No additional conclusions are deemed necessary to explain a conclusion of obviousness. As such, in view of the guidance of MPEP 2143(I)(B), an ordinarily skilled artisan at time of filing would have been motivated to have substituted the KLK1 of SEQ ID NO: 2 of Ma in replacement for the KLK1 in Charles.
As discussed, Charles and Tang teaches substitution of N141 to another amino acid residue to produce a KLK1 recombinant variant that is a double glycosylated isoform of KLK1. Upon use of a recombinant KLK1 having SEQ ID NO: 2 of Ma, the same motivation to substitution position N141 thereof applies as discussed above. As discussed, Tang teaches a substitution of Asn(N) to Glu(E). “It is well known in the art that the polypeptide may be modified by substituting, inserting, deleting and/or adding one or more amino acids while the enzymatic activity is maintained. For example, it is common to substitute one amino acid at a given position with a chemically equivalent, amino acid without affecting the function and property of the protein. Therefore, it is anticipated that a functionally equivalent product may be produced by substituting one negatively charged residue with another or substituting one positively charged residue with another.” Ma, para. [0075]. An ordinarily skilled artisan at time of filing (as evidenced by Ma) is aware of the identity of the 20 proteinogenic amino acids including the negative amino acids (i.e. acidic) Glu(E) and Asp(D). For example, SEQ ID NO: 1 of Charles indicates the identity of all 20 proteinogenic amino acids wherein an ordinarily skilled artisan at time of filing would recognize the amino acid and structure associated with each of the symbols of an amino acid sequence listing (i.e., A(Ala), C(Cys), D(Asp), E(Glu), etc.). As such, an ordinarily skilled artisan at time of filing would have been motivated to mutate position N141 to any acidic amino acid residue that would not be subject to glycosylation including either Glu or Asp. Modification of the recombinant KLK1 of SEQ ID NO: 2 of Ma to have a N141D substitution yields a recombinant KLK1 variant identical to recited SEQ ID NO: 2 as recited in claim 14.
Regarding claims 15-16, Ma directly teaches that pegylation of any recombinant KLK1 is beneficial for treatment of ischemic stroke (i.e. cerebral infarction). “Technical problems to be solved: the present invention provides a PEGylated tissue kallikrein (KLK1) having a high biological activity, a long half-life, and a low immunogenicity, and use thereof in the preparation of drugs for treating mild to moderate acute thrombotic cerebral infarction.” Ma, para. [0007]. “Several mono-PEGylated products of KLK1 referred to as “SC-PEG5000-KLK1, Y-PALD-20K-KLK1, Y-PALD-30K-KLK1, Y-PALD-40K-KLK1” herein may be collectively referred to as PEG-KLK1 or the conjugate.” Ma, para. [0069].
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As such, Ma directly suggest at motivates to an ordinarily skilled artisan at time of filing that any recombinant KLK1 consistent with the teachings thereof be conjugated to PEG including Y-PALD-30K as recited in at least claim 15.
“In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists.” MPEP 2144.05. The formula in para. [0070] of Ma is consistent with the structure for “Y-PALD-30K” set forth in claim 16. Ma directly teaches “Y-PALD-30K” as an embodiment wherein “30K” is understood as a reference to molecular weight. The range for “n” for the formula in para. [0070] of Ma set forth to be 277-445 overlaps the value of 335 in claim 16 for Y-PALD-30K such that “a prima facie case of obviousness exists.” MPEP 2144.05. Similarly, the formula for Y-PALD-30K in claim 16 embodies p=2 in reference to the formula in para. [0070] of Ma setting forth p as an integer from 1 to 3 such that “a prima facie case of obviousness exists” for an overlapping or lie within range as recited in claim 16. As such, an ordinarily skilled artisan at time of filing would have been motived to modify any recombinant KLK1 for treatment of ischemic stroke to be PEGylated including PEGylation with a Y-PALD-30K meeting the structural formula for the same as recited in claim 16.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 3 and 13-16 (all pending claims) are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 2 and 4-17 of copending Application No. 18/710,640 in view of Charles (U.S. 2013/0323222 A1), Tang et al. (Expression, Crystallization, and Three-dimensional Structure of the Catalytic Domain of Human Plasma Kallikrein, J. Biol. Chem. 280, 2005, 41077-89), Alexander-Curtis et al. (Human tissue kallikrein in the treatment of acute ischemic stroke, Therapeutic Adv. Neurological Disorders 12, 2012, 1-15) (previously cited) and Tatemichi et al. (Cognitive impairment after stroke, J. Neurology, Neurosurgery Psychiatry 57, 1994, 202-207) (previously cited) and Ma et al. (U.S. 2017/0049864 A1).
Application No. 18/710,640 is published as Ma et al. (U.S. 2025/0011747 A1). The teachings of Charles, Tang, Alexander-Curtis and Tatemichi discussed above are incorporated herein by reference.
The copending claims recite:
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SEQ ID NO: 4 of the copending claims is identical to recited SEQ ID NO: 2. Copending claim 2 is understood as directly suggesting a recombinant primate (human) KLK1 having a mutation in the sequence N141-F142-S143 as exemplified in SEQ ID NO: 4 of copending claim 10. Copending claim 14 recites that the recombinant KLK1 is pegylated with a structure consistent with and anticipates M-SPA-10K as recited in claim 16 with n/m being 225.
The copending claims do not explicitly state administering an effective amount of such pegylated recombinant KLK1 mutant with substitution N141D to a subject having post-stroke cognitive impairment to treat post-stroke cognitive impairment, although copending claim 17 recites a method of treating acute ischemic stroke by administering to a subject an effective amount of the pegylated KLKI mutant of copending claim 13.
The use of KLK1 to treat strokes and neurological symptoms resulting therefrom is well-established in the prior art.
Alexander-Curtis, abstract, states:
Acute ischemic stroke (AIS) remains a major cause of death and disability
throughout the world. The most severe form of stroke results from large vessel occlusion
of the major branches of the Circle of Willis. The treatment strategies currently available in
western countries for large vessel occlusion involve rapid restoration of blood flow through
removal of the offending blood clot using mechanical or pharmacological means (e.g. tissue
plasma activator; tPA). This review assesses prospects for a novel pharmacological approach
to enhance the availability of the natural enzyme tissue kallikrein (KLK1), an important
regulator of local blood flow. KLK1 is responsible for the generation of kinins (bradykinin and
kallidin), which promote local vasodilation and long-term vascularization. Moreover, KLK1 has
been used clinically as a direct treatment for multiple diseases associated with impaired local
blood flow including AIS. A form of human KLK1 isolated from human urine is approved in the
People’s Republic of China for subacute treatment of AIS. Here we review the rationale for
using KLK1 as an additional pharmacological treatment for AIS by providing the biochemical
mechanism as well as the human clinical data that support this approach
“[T]he treatment period for all studies lasted between 7 and 21 days. The analysis showed that uKLK1 treatment was significantly associated with an improvement in neurological outcomes and a reduction in death and dependency at the 3-month follow up in the two well-controlled trials.” Alexander-Curtis, page 7, right col. Impairment of cognitive function following ischemic stroke is common known neurological symptom. See Tatemichi, abstract (Cognitive function was examined in 227 patients three months after admission to hospital for ischaemic stroke, and in 240 stroke-free controls, using 17 scored items that assessed memory, orientation, verbal skills, visuospatial ability, abstract reasoning, and attentional skills.) As such, as far as Alexander-Curtis teaches the administration of kallikrein I to subjects following ischemic stroke with an expectation in improvement of neurological outcomes, any observation that the described improvement in neurological outcomes includes ameliorating cognitive impairment (post-stroke cognitive impairment) is “recogni[tion] another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious.” MPEP 2145(II).
Further, as discussed above, Ma teaches “Technical problems to be solved: the present invention provides a PEGylated tissue kallikrein (KLK1) having a high biological activity, a long half-life, and a low immunogenicity, and use thereof in the preparation of drugs for treating mild to moderate acute thrombotic cerebral infarction,” wherein the KLK1 taught by Ma is over 99% identical in sequence to the sequence identifiers set forth in copending claim 10. Ma, para. [0007].
As such, an ordinarily skilled artisan at time of filing would have been motivated to administer the pegylated recombinant KLK1 mutant as recited in any of the copending claims in the same manner as taught by Alexander-Curtis in order to treat and improve neurological outcomes in ischemic stroke that includes improvement of post-stroke cognitive impairment as discussed. An ordinarily skilled artisan at time of filing would readily understand that any recombinant KLK1 mutant administered should be done in an amount that results in a neurological and/or cognitive improvement that would constitute administering to the subject an effective amount of the recombinant KLK1 mutant.
This is a provisional nonstatutory double patenting rejection.
Conclusion
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/TODD M EPSTEIN/Primary Examiner, Art Unit 1652
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