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
This application filed 13 May 2024, is a 371 national stage entry of PCT/EP2022/083902, filed 30 November 2022. Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been filed in parent Application No. EP21306677.2, filed on 01 December 2021.
Information Disclosure Statement
Two information disclosure statements (IDS) submitted on 13 May 2024 are acknowledged and have been considered. Examiner notes the two IDSs are identical thus, one of is a duplicate of the other.
Status of the Claims
Acknowledgement is made of claims in the filed Application 18/709,695 with original claims 1-15. No amendments, cancellations or additions have been made to the originally-filed claims. Thus, claims 1-15 represent all the claims currently under consideration.
Claim Objections
Claims 11 and 12 are objected to because of the following informalities.
(i) Claim 11 recites “….wherein the IRA inhibitor”. The letter P is missing in what should be “IRAP inhibitor”. Applicant is requested to correct the error.
(ii) Claim 12 erroneously contains unmatched closing parentheses following the terms, “spondylitis)” (on page 57 - line 11), and “telangiectasia) ( on page 59, line 31). Applicant is requested to correct and amend appropriately.
Appropriate correction is required.
Claim Rejections - 35 USC § 112b
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 2 and 14 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.
Claims 2 and 14 recite the phrases “including” on page 57 – lines 13, 16, page 58 lines 5, 6, 11, 18, page 59- line 4; and “such as” on page 57 - lines 11, 15, 28, page 58 lined 3, 15, 23, 26, page 59 – lines 2, 4, 17, 19, 23, 29, page 60 lines 1, 6, 28 and page 61 – line 7 and page 69 (claim 14).
The phrases render the claims indefinite because they encompass elements not actually disclosed (those encompassed by “including’ and ‘such as”), thereby rendering the scope of the instant claim unascertainable. Description of preferences is properly set forth in specification rather than the claims. If stated in the claims, preferences may lead to confusion over the intended scope of a claim. See MPEP § 2173.05 (d).
Claim 2 recites phrases in parenthesis, for example on page 58 – lines 5, 6, 7, 11 and 19. This renders the claim indefinite because it is unclear whether what is recited in the parentheticals broadens or narrows the scope of the claimed invention. Applicant is requested to remove the parentheticals and amend the claim so as to particularly point and distinctly claim what is considered as the invention, without using parentheticals.
Examiner has identified the parentheticals on page 58 as representative examples and has not identified every occurrence throughout the claim. Applicant is requested to review the claim in its entirety and remove all such parentheticals as appropriate.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-15 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Chai et al., 2018, U.S. Patent No. 10,100,311 B2; Date of Patent: October 16, 2018, hereon after ‘311.
Reference ‘311 discloses methods for treatment with compounds that are inhibitors of insulin-regulated aminopeptidase (IRAP) and inhibit IRAP mediated signalling (abstract). The reference teaches IRAP inhibitor(s) directly inhibit(s) the enzymatic activity of IRAP preferably by binding to the active site of IRAP and more preferably the inhibitor competes with or prevents the binding of a substrate of IRAP for binding to IRAP (col 2). Notably, while the invention in ‘311 teaches methods for the treatment of fibrosis, in particular cardiac fibrosis (abstract), it further states that fibrosis is often preceded by inflammation due to infiltration of inflammatory cells during the initial phase of the injury and the subsequent production of multiple cytokines. It further teaches that aging elevates reactive oxygen species (ROS), which exacerbates inflammation (col 75, lines 10-35).
Regarding instant claim 1, using WT and IRAP–/– mice, 311 discloses; (i) genetic deletion or pharmacological inhibition of IRAP prevents angiotensin II-induced increase in cardiac reactive oxygen species and inflammatory markers (col 69) and (ii) IRAP inhibition decreases cardiac reactive oxygen species (ROS) and inflammatory mediators downstream of NFKB, collectively pushing towards an anti-inflammatory phenotype thus contributing to overall cardiac and vascular improvement in aging (col 14). Additionally, for an example, ‘311 defines pulmonary fibrosis as – “the scar tissue replaces healthy tissue and causes inflammation - this chronic inflammation is, in turn, the prelude to fibrosis” (col 35 line 5-9).
Regarding instant claim 2, ‘311 teaches IRAP inhibitors for treatment of diseases or conditions associated with upregulation of IRAP expression and /or activity and notably discloses diseases/ conditions that overlap diseases recited in the instant claim 2 – namely, rheumatoid arthritis, Alzheimer’s disease, chronic asthma, multiple sclerosis, diabetic nephropathy, IgA nephropathy or scleroderma, scleroderma or systemic sclerosis, cardiomyopathy, a chronic systemic autoimmune disease, hepatitis B, C or D virus infections, cirrhosis, and associated conditions such as chronic viral hepatitis, primary biliary cirrhosis (PBC), biliary cirrhosis, autoimmune hepatitis, emphysema, chronic obstructive pulmonary disease, psoriasis, among others (col 35 and 36). Importantly, ‘311 provides proof-of-principle, in vivo and in vitro, studies that demonstrate IRAP deficiency and direct pharmacological inhibition of IRAP were effective in preventing Angiotensin II-mediated cardiac and vascular fibrosis and inflammation; further states that results from the studies done underline the potential clinical effectiveness of targeting IRAP (Example 2 – col 69).
Regarding instant claim 3, ‘311 teaches IRAP inhibitors for treatment of chronic asthma, diffuse parenchymal lung disease (col 36), hypersensitivity pneumonitides, pulmonary fibrosis caused by inhalation of inorganic dust, pulmonary fibrosis caused by an infectious agent, pulmonary fibrosis caused by inhalation of noxious gases, aerosols, chemical dusts, fumes or vapours, and drug-induced interstitial lung disease, or pulmonary hypertension (col 33).
Regarding instant claim 4, ‘311 teaches the IRAP inhibitors disclosed treat conditions caused by reaction to radiation, drug reaction and exposure to toxins (col 33).
Regarding instant claim 5; ‘311 discloses an inhibitor of IRAP of generic formula – Formula (I) – (‘311 – claim 16, col 79);
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The structure of Formula (I) disclosed in ‘311 and the definition of the variables A, X, R1, R2, R3-R6 and Y completely overlap with compound of Formula (I) in the instant claim. ‘311 further teaches an embodiment HFI-419, that reads on generic Formula (I) in the instant application as follows; A is heteroaryl, Y is H, X is O, R3, R4, and R6 are each H and R5 is hydroxy, R1 is NHCOCH3 (or NHCOR8) and R2 is CO2CH2CH3 (or CO2R9) ('311 - col 49 & claim 17-col 80).
Regarding instant claim 6, ‘311 discloses compound, HFI-419 (shown above), that is identical to claimed compound in the instant application ('311 - col 49 & claim 17 – col 80).
Regarding instant claim 7, ‘311 teaches an identical compound of formula (II) (claim 18 - column 80);
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which is identical to the instant claim both in structure and definitions of all the variables A, R1, R2, R3, and NRARB. ‘311 further provides an embodiment, compound 1 (‘311 - col 50 & claim 18 - col 80), that reads on the instant claim’s generic Formula (II) - where A is a substituted aryl, R1, is CN, R2 is acyl, R3 is alkyl, and RA and RB are each H in NRARB.
Regarding instant claim 8, ‘311 discloses compound 1 (discussed above), that is identical to structure claimed in the instant application ('311-col 50 & claim 18 - col 80).
Regarding instant claim 9, ‘311 provides examples shown in the reference that are identical to all the compounds recited in the instant claim ('311 - col 51 to col 65) – sample examples are shown below.
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Regarding instant claim 10, ‘311 teaches a compound of Formula (III) or a pharmaceutically acceptable salt, solvate or prodrug thereof (311 – col 21 and claim 20 - col 82). Compound of formula (III) as disclosed in '311 is identical to the instant claimed compound both in structure and in all definitions of the variables R1, n, m, and W. ’311 further provides an embodiment (col 22 and claim 21 – col 82), that reads on the generic formula (III) in the instant application.
Regarding instant claim 11, ‘311 teaches an IRAP inhibitor with an identical structure as claimed in the instant application (col 22 and claim 21 – col 82).
Regarding instant claim 12, ‘311 teaches an IRAP inhibitor with identical structures as claimed in the instant claim ('311 claim 23 - col 83).
Regarding instant claim 13, '311 discloses the IRAP inhibitor is preferably chosen from a group including HFI-419 (abstract). Additionally, '311 provides examples of mice experiments performed with compound HFI-419 that display IRAP inhibition (col 71-72).
Regarding instant claim 14, '311 teaches the IRAP inhibitor is an inhibitor of IRAP expression and inhibitor may be an interfering RNA e.g. siRNA (col 15 & 33).
Regarding instant claim 15, '311 describes IRAP inhibitor assays for example aminopeptidase activity or substrate degradation. Further, the assay of substrate degradation maybe degradation of peptide substrates with examples provided (col 15).
Per MPEP § 2112.01, products of identical chemical composition cannot have mutually exclusive properties. "In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present.
‘311 teaches the disclosed compounds or pharmaceutically acceptable salts and methods of treatment of fibrosis, in particular cardiac fibrosis. ‘311 reveals fibrosis is often preceded by inflammation due to infiltration of inflammatory cells during the initial phase of the injury and the subsequent production of multiple cytokines. Additionally, ’311 discloses IRAP inhibition decreases cardiac reactive oxygen species (ROS) and inflammatory mediators downstream of NFKB collectively pushing towards an anti-inflammatory phenotype.
As stated above, a chemical composition and its properties are inseparable, one would expect the compound(s) disclosed in ‘311 to have the same properties of treating an inflammatory disease as claimed in the instant application.
Accordingly, instant claims 1-15 in the instant application were anticipated by U.S. Patent 10,100,311 B2.
Claims 1-6, 12-13 and 15 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Barlow and Thompson, 2020, (Barlow N and Thompson PE, IRAP Inhibitors: M1-Aminopeptidase Family Inspiration, Frontiers in Pharmacology, Vol.11, Article 585930, page 1-8; Published 25 September 2020, Cited in the IDS), hereon after Barlow.
Regarding instant claim 1, Barlow teaches IRAP, is a member of M1 aminopeptidase family, that shares numerous structural features with other M1 aminopeptidases (abstract). Barlow points out the pleiotropic character IRAP makes it a potential therapeutic target for many therapeutic applications (page 1). The review discusses scaffolds of IRAP inhibitors developed for applications targeting IRAP / M1 aminopeptidases family (Fig 1 & 2 and Table 1). In particular, Barlow points out, M1 aminopeptidase - non-canonical binding site ligand, leukotriene A4 hydrolase (LTB4) has attracted attention as a therapeutic target for inflammatory diseases; “LTB4 is an inflammatory lipid and thus blocking its formation would be a therapeutic option” (page 6). Notably, Barlow highlights that the enzyme has also been shown to process a variety of peptides most notably Pro-Gly-Pro a collagen degradation product which is a pro-inflammatory chemotactic peptide. Barlow discusses inhibitors that are in clinical trial for treatment of cystic fibrosis (page 6).
Furthermore, the ‘Background of the Invention’ in instant specification (page 1), points out that in a second phase after activation, mast cells synthesize and secret large amounts of pro-and anti-inflammatory cytokines, chemokines, growth factors, prostaglandins and leukotrienes (Instant Specification, page 1 lines 13-15).
Regarding instant claim 2, Barlow teaches IRAP inhibitors as therapeutic targets for inflammatory diseases conditions recited in the instant claim, namely, Alzheimer’s disease and immune disorders (abstract), obesity-related disorders, cerebral ischemia, thrombosis and inflammatory disease (page 6).
Regarding instant claim 3 and 4, Barlow teaches IRAP as a target particularly for inflammatory disease and IRAP inhibitors as drug targets for cancer immunotherapy or control of autoimmunity (page 2).
Regarding instant claims 5 and 6, Barlow discloses compound 6 (Fig. 1, page 2), which reads on instant generic Formula (II), (instant claim 5) and is completely identical to the claimed compound (instant claim 6).
Regarding instant claims 12-13 and 15, Barlow discusses the first IRAP small molecule inhibitor series to be described were benzopyrans including HFI-419, compound 6 (Fig. 1 – page 2 & 3), which is identical to the claimed compound in the instant application (instant claims 12 and 13). Additionally, Barlow notes IRAP inhibitors function through degradation of IRAP for example in the mechanism for increased learning, in AngIV and in treatment of cystic fibrosis (instant claim 15).
Therefore, instant claims 1-6, 12-13 and 15 were anticipated by Barlow and Thompson, 2020.
Claims 1-6, 10-13 and 15 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Georgiadis et al., 2020, (Georgiadis et al., The discovery of Insulin-Regulated Aminopeptidase (IRAP) Inhibitors: A Literature Review. Frontiers in Pharmacology, Vol.11, Article 585838, page 1-8; Published 23 September 2020), hereon after, Georgiadis.
Regarding instant claims 1-4, Georgiadis’ review teaches IRAP inhibitors have been applied in treatment of inflammatory autoimmune diseases. Georgiadis highlights pharmacological inhibition of IRAP for treatment of memory disorders, neurodegenerative diseases, cancer immunotherapy as well as inflammatory autoimmune diseases.
Regarding instant claims 5, 6 and 13, Georgiadis discusses a prior-known compound HFI-419 (Fig. 2, page 5), which reads on instant Formula (II), (instant claim 5) and is identical to the claimed compound (instant claim 6 and 13).
Regarding instant claims 10-12 and 15, Georgiadis discusses a prior known compound, HA08 (Fig. 1 page 3) which is known to display excellent IRAP potency. HA08 is identical to instant claimed compound (instant claim 11) and reads on the instant generic Formula (III) in the instant invention (instant claim 10).
The review also discusses two prior known compounds AL-40 (Fig. 1 – page 3) and HFI-435 (Fig. 2- page 4). AL-40 and HFI-435 are identical to compounds claimed in the instant application (instant claim 12). The review points out that HFI-419, AL-40 and HFI-435 were selected from other analogs of benzopyran, as most active and promising lead compounds. Additionally, Georgiadis teaches IRAP inhibitors function through degradation of IRAP (page 2-4) – instant claim 15.
Therefore Georgiadis et al., 2020, anticipates the instant claims 1-6, 10-13 and 15 in the instant application.
Claims 1-3, 7-9 and 14-15 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Chai et al., 2016, WO 2016/179645 A1, (Published, 17 November 2016), hereon after ‘645.
Regarding instant claims 1-3, ‘645 discloses 4H-pyran compounds, their compositions and methods of using them as inhibitors of IRAP for treatment of Alzheimer’s disease, prevention of memory and cognitive disorders (abstract). ‘645 reveals the 4H-pyran compounds were found to exhibit IRAP inhibitory activity for treating symptoms and/ or pathological events characterized by unwanted or excessive Aβ accumulation and deposition or a pro-inflammatory response (page 5). ‘645 discloses in vitro assays carried out to test the effects of the IRAP inhibitors in pro- and anti-inflammatory cytokines (Example 7 – page 71). Furthermore, the reference informs artisans, the compounds and methods disclosed are useful for disorders and conditions where undesirable or excessive IRAP aminopeptidase activity is implicated or involved (page 32).
Regarding instant claims 7-9, ‘645 teaches a generic compound of formula (I), compounds, their pharmaceutically acceptable salts, solvates and prodrugs – the generic compound of formula (I) and its defined variables overlap completely with the instant claimed Formula (II) - instant claim 7 - (‘645, page 5 & claim 1, page 75).
‘645 further discloses an embodiment, the ammonium salt of compound 15 (‘645 - page 63), which reads on the instant claimed compound of Formula (II) and is identical to the instant claimed compound (instant claim 8).
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Additionally, ‘645 teaches exemplified embodiments and their IRAP enzymatic test assays results. The examples which include compounds 11k, 11m, 11n, 11o, 11p, 11s, 11t, 11u, 13b, 14b, 14d, 14e, 15a, 15b, 15e, 15i, 15j, 15k,15g, 16, 17a and 17b are identical/ overlap with instant claimed compounds (instant claim 9) (‘645 page 43-59).
Regarding instant claims 14-15, ‘645 discloses assays with IRAP inhibitors and isolated RNA. Furthermore, ‘645 highlights the IRAP inhibitory activity of the compounds in the reference was determined through in vitro assay(s) which measured the ability of the compound(s) to inhibit the aminopeptidase activity of IRAP, by assessing the rate or extent of cleavage or degradation of an IRAP aminopeptidase substrate such as Leu-β-naphthylamide or Leu-4-methylcoumaryl-7-amide (‘645 page 32 & 71).
Therefore, instant claims 1-3, 7-9 and 14-15 were anticipated by Chai et al., 2016, WO 2016/179645 A1.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-15 are rejected under 35 U.S.C. 103 as being unpatentable over Chai et al., 2018, (U.S. Patent No. 10,100,311 B2; Date of Patent: October 16, 2018), hereon after ‘311, in view of Henderson et al., 2020, (Henderson et al, Fibrosis: From mechanism to Medicines, Nature, 587 (7835) page 555-566; Published 25 November 2020), hereon after, Henderson and Ansar, 2016, (Ansar W and Ghosh S, 1st Ed., Biology of C Reactive Protein in Health and Disease; Publisher Springer. ISBN: 978-81-322-2680-2 - Chapter 4; Published June 10, 2016), hereon after, Ansar.
Regarding instant claims 1-15; The teachings of ‘311, as set forth in the above 35 U.S.C. 102 Rejection are incorporated herein. ‘311 discloses IRAP inhibition with HFI-419 reproduced effects on inflammatory mediators; pro-and anti-inflammatory cytokines were differentially regulated in HFI-419 treated WT-mice. Additionally, there were increases in anti-inflammatory cytokines providing anti-inflammatory effect mediated by IRAP inhibition that mirrored the phenotype evident in aged IRAP–/– mice (Table 1 – col 71).
How prior art differs from instant claims: ‘311 teaches methods of treatment of fibroses using IRAP inhibitors. In addition, the fibrosis is selected from cardiac fibrosis, liver fibrosis, kidney fibrosis, vascular fibrosis, lung fibrosis and dermal fibrosis. Instant invention claims a method for treating an inflammatory disease (instant claim 1).
Henderson teaches fibrosis is not a disease but rather an outcome of tissue repair response that becomes dysregulated following many types of tissue injury most notably during chronic inflammatory disorders (page 555).
In addition, Ansar in discussing inflammation teaches the following (i) unresolved acute inflammation response leads to development of chronic inflammation by persistent injury or infection (e.g. ulcer, tuberculosis (TB)); (ii) prolonged exposure to toxic agents like silica and autoimmune diseases like rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), (iii) chronic inflammation leads to tissue destruction, fibrosis, and necrosis (page 70 & Fig 4.4, page 73). Ansar further teaches the key role played by pro- and anti-inflammatory cytokines in inflammatory responses and treatment of inflammatory diseases such as autoimmune diseases, cancer, cardiovascular disease, asthma, among others (page 76-77 & 83-95).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filling date of the claimed invention to arrive at the claimed invention in view of prior art with reasonable expectation of success.
Per MPEP § 2144.07, a prima facie case of obviousness exists for the selection of known material based on its suitability for its intended use. In addition, per MPEP § 2144.05(I), a prima facie case of obviousness exists when the claimed invention overlaps with, or is close to prior art.
‘311 teaches generic compounds of formula (I), formula (II) and formula (III), along with embodiments that overlap completely with the claimed compounds in instant application for treatment of fibrosis. ‘311 teaches claimed compounds reduced inflammatory cytokines and the IRAP inhibitors were effective in preventing Angiotensin II-mediated cardiac and vascular fibrosis and inflammation in mice.
Henderson and Ansar teach acute and chronic inflammation is at the root of the condition known as fibrosis. Ansa teaches the pro-and anti-inflammatory cytokines are involved in inflammatory responses and indicates inflammatory cytokines similar to those cited in ‘311.
Accordingly, it would have been obvious to claim a method of treating an inflammatory disease, in a patient in need thereof, comprising administering to the patient a therapeutic amount of an IRAP inhibitor (instant claim 1), a method where the inflammatory disease is selected from the diseases as recited (instant claim 2 -4), a method where the IRAP inhibitor has a structure as recited (instant claim 5-13), where the IRAP inhibitor is an inhibitor of IRAP expression such as siRNA or antisense oligonucleotide (instant claim 14) and where the IRAP inhibitor leads to destabilization and /or degradation of IRAP (instant claim 15).
One of ordinary skill in the art would have been motivated to arrive at the claimed invention because (i) The claimed compound(s) were known from prior art (ii) in vivo and in vitro assays and pharmacological data of the claimed compounds was known in prior art (ii) prior art teaches the disclosed IRAP inhibitors for treatment of fibrosis and further from prior art it is known that chronic inflammation leads to fibrosis (iii) prior art discloses IRAP inhibitors reduce inflammatory cytokines and/or markers, and (iv) prior art teaches pro- and anti-inflammatory cytokines implicated in fibrosis are the same ones implicated in inflammatory diseases.
Conclusion
Claims 1-15 are rejected. No claim is allowed.
Communication
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PAULINE ONDACHI whose telephone number is (571)272-9419. The examiner can normally be reached Mon - Fri 8:00 am - 5:00 pm EST.
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/P.O./Examiner, Art Unit 1627
/Kortney L. Klinkel/Supervisory Patent Examiner, Art Unit 1627
