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 .
DETAILED ACTION
Election/Restrictions
Claims 1-24 are pending.
Applicant’s election without traverse of Group I, claims 1-15, species lung fibrosis, F1, TGF-beta, oral, anti-TGF-beta, in the reply filed on 10/10/25 is acknowledged.
Claims 16-24 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 10/10/25.
Claims 1-15 are examined on the merits.
Claim Objections
Claims 1-15 are objected to because of the following informalities: Claim 1 recites “Caesalpinia sappatin” at line 6, which is incorrect. The correct spelling should be “Caesalpinia sappan”.
All other cited claims depend directly or indirectly from objected claims and are, therefore, also, objected for the reasons set forth above.
Claim Rejections –35 USC § 112, 2nd
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 1-15 are rejected under 35 U.S.C. 112, second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which applicant regards as the invention.
Claim 1 (at lines 6-12) recites parenthetical expression "(A16)", “(B8)” etc. Claim 1 recites “(and SMAD2/3)”, “(and NF-KB)”, and “(and STAT3)” at lines 3-4 from the bottom. The metes and bounds of Claim 1 are rendered vague and indefinite by the parenthetical recitation of because it is unclear as to whether the limitation is part of the instantly claimed subject matter.
Claims 2-4 are rejected for the same reason.
Therefore, the metes and bounds of claims are rendered vague and indefinite. The lack of clarity renders the claims very confusing and ambiguous since the resulting claims do not clearly set forth the metes and bounds of the patent protection desired.
All other cited claims depend directly or indirectly from rejected claims and are, therefore, also, rejected under U.S.C. 112, second paragraph for the reasons set forth above.
Claim Rejections –35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-6, 8, and 14 are rejected under 35 U.S.C. 102 (a)(1) as being anticipated by Kilic et al (Kilic et al, Protective and Therapeutic Effect of Apocynin on Bleomycin-Induced Lung Fibrosis in Rats. Inflammation, (14 Dec 2014)), as evidenced by Fan et al (Fan et al, Apocynins A-D: new phenylpropanoid-substituted flavan-3-ols isolated from leaves of Apocynum venetum (Luobuma-Ye). Chemical and Pharmaceutical Bulletin (1999), Volume 47, Number 7, pp. 1049-1050)*.
Kilic et al teach we aimed to investigate the preventive and therapeutic effect of apocynin (APO) (thus an active chemical present in the claimed herbal extract of Apocynum venetum, see Fan et al for details) on bleomycin (BLC)-induced lung injury in rats. Rats (thus a mammal, thus claim 15 is met) were assigned into groups as follows: control group; APO group, 20 mg/kg APO was given intraperitoneal for 29 days (thus liquid, thus claim 8 is met); BLC-1 and BLC-2 groups, a single intratracheal injection of BLC (2.5 mg/kg); APO+BLC-preventive group, 20 mg/kg APO was administered 12 h before the intratracheal BLC injection and continued for 14 days; BLC+APO-treatment group, 20 mg/kg APO was given on the 14th day after the intratracheal BLC injection and continued to sacrifice. The BLC-1 group was sacrificed on the 14th day of BLC administration to validate BLC-induced lung inflammation and fibrosis on the 14th of study initiation. All other groups were sacrificed on the 29th day after BLC administration. The semiquantitative histopathological assessment, tissue levels of malondialdehyde (MDA), superoxide dismutase, catalase (CAT), glutathione peroxidase (GPx), reduced glutathione (GSH), total antioxidant capacity, total oxidant status (TOS), and oxidative stress index (OSI) were measured. An addition to the serum myeloperoxidase (MPO), the cell count and cytokines (IL-1β, IL-6, and IL-8) of bronchoalveolar lavage (BAL) fluid were assayed. BLC-provoked histological changes were significantly detected compared to the control group. APO restored these histological damages in different quantity in the treatment and prevention groups. BLC caused a significant decrease in GSH, CAT, and GPX, which were accompanied with significantly the increased MDA, TOS levels, and OSI in the lung tissue concomitant with increased levels of the cellular account and proinflammatory cytokines in the BAL fluid. Otherwise, APO administration, both before and after BLC, reversed all biochemical markers and cytokine as well as histopathological changes induced by BLC. Interestingly, APO treatment reversed MPO activity in serum increased by BLC. In this study, both protective and therapeutic effects of APO against BLC-induced lung fibrosis (thus the claimed disease or disorder in claim 1 c, thus claims 2-6 are met) were demonstrated for the first time (see Abstract) (thus claim 1 is met).
Fan et al teach four new phenylpropanoid-substituted flavan-3-ols called apocynins A-D
were isolated from the leaves of A. venetum [Trachomitum venetum], together with 2 known phenylpropanoid-substituted flavan-3-ols, catechin-[8,7-e]-4α-(3,4-dihydroxyphenyl)-dihydro-2(3H)-pyranone and cinchonain Ia, and 4 known flavan-3-ols, (-)-epicatechin, (+)-catechin, (-)-epigallocatechin, and (+)-gallocatechin. Their structures were elucidated on the basis of spectral analysis, including 2D NMR and CD spectra. They showed hepatoprotective activity against smallcap~D-galactosamine (smallcap~D-GalN)/tumour necrosis factor-α (TNF-α)-induced cell death in primary cultured mouse hepatocytes (see Abstract).
Thus as evidenced by Fan et al, apocynin is the active ingredient of the claimed extract of Apocynum venetum.
Therefore, the reference is deemed to anticipate the instant claim above.
*This reference is cited merely to relay an intrinsic property and is not used in the basis for rejection per se.
Claims 1-3, 5, 6, 8, and 12-14 are rejected under 35 U.S.C. 102 (a)(1) as being anticipated by Ye et al (Ye et al, Neuroprotective effects of salvianolic acid B on secondary spinal cord damage. Neural Regeneration Research, (JAN 25 2011) Vol. 6, No. 3, pp. 188-192).
Ye et al teach Salvianolic acid B (Sal B), an effective ingredient of Danshen (salviamiltiorrhiza root) (active chemical present in the at least one herbal extract), has been shown to exhibit anti-oxidative and anti-inflammatory effects. The present study investigated whether Sal Bhas a neuroprotective effect on secondary spinal cord injury (thus a method for treating or preventing a disease or disorder, thus claims 1-2 are met) when administrated alone. In addition, the effects of Sal B on attenuating expression of tumor necrosis factor-alpha (TNF-alpha) (thus claims 1 and 2 are met) following acute spinal cord injury were analyzed, as well as the effects of combined treatment of Sal B and etanercept (thus claims 12 and 13 are met) Immunohistochemical staining demonstrated that Sal B significantly reduced matrix metalloproteinase-1 and c-Fos expression at 24 hours after spinal cord injury, and decreased tissue edema was detected using the dry-wet weight method at 3 days after injury. In addition, Sal B significantly promoted recovery of motor function in rats. These effects were most significant at a dose of 20 mg/kg Sal B. At 24 hours after spinal cord injury, reverse transcription-polymerase chain reaction and western blot assay results showed that Sal B, etanercept, or the combination significantly suppressed increased TNF-a mRNA and protein expression, although the combination resulted in more significant outcomes. These results suggested that Sal B exerted neuroprotective effects against secondary spinal cord injury by reducing expression of matrix metalloproteinase-1, c-Fos, and TNF-alpha (thus related to the activity of TNF-alpha). Moreover, Sal B combined with etanercept resulted in more significant anti-inflammatory effects (see Abstract). Ye et al teach a total of 90 healthy adult female Sprague Dawley rats (thus claim 14 is met) were used, and Sal B and/or etanercept groups were intraperitoneally administered 20 mg/kg Sal B (thus a liquid, thus claim 8 is met) and/or 5 mg/kg etanercept at 30 min after spinal trauma, respectively (page 191, 1st column, 3rd and 4th paragraph).
Therefore, the reference is deemed to anticipate the instant claim above.
Claim Rejections –35 USC § 103
The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained through the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
Claims 1-15 are rejected under 35 U.S.C. 103(a) as being unpatentable over Kilic et al and Fan et al as applied to claims 1-6, 8, and 14 above, and further in view of Altintas (Altintas, Protective Effect of Infliximab, a Tumor Necrosis Factor-Alfa Inhibitor, on Bleomycin-Induced Lung Fibrosis in Rats. Inflammation, (1 Feb 2016) Vol. 39, No. 1, pp. 65-78).
The teachings of Kilic et al and Fan et al are set forth above and applied as before.
The teachings of Kilic et al and Fan et al do not specifically teach oral administration, the claimed dosage, administration frequency, additional anti-TGF-beta agent infliximab, or a human subject.
Altintas teaches we aimed to investigate the preventive effect of Infliximab (IFX) (thus claim 13 is met), a tumor necrosis factor (TNF)-α inhibitor, on bleomycin (BLC)-induced lung fibrosis in rats. Rats were assigned into four groups as follows: I-BLC group, a single intra-tracheal BLC (2.5 mg/kg) was installed; II-control group, a single intra-tracheal saline was installed; III-IFX + BLC group, a single-dose IFX (7 mg/kg) was administered intraperitoneally (i.p.), 72 h before the intra-tracheal BLC installation; IV-IFX group, IFX (7 mg/kg) was administered alone i.p. on the same day with IFX + BLC group. All animals were sacrificed on the 14th day of BLC installation. Levels of tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-β, interleukin (IL)-6, periostin, YKL-40, nitric oxide (NO) in rat serum were measured, as well as, myeloperoxidase (MPO), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) activity, and reduced glutathione (GSH), hydroxyproline, malondialdehyde (MDA) content in lung homogenates. Lung tissues were stained with hematoxylin and eosin (H&E) for quantitative histological evaluation. The inducible nitric oxide synthase (iNOS) expression and cell apoptosis in the lung tissues were determined quantitatively by immunohistochemical staining (INOS) and by TUNNEL staining, respectively. BLC installation worsened antioxidant status (such as SOD, CAT, GPx, GSH, MPO), while it increased the serum TNF-α, TGF-β, IL-6, periostin, YKL-40, and lipid peroxidation, and collagen deposition, measured by MDA and hydroxyproline, respectively. IFX pretreatment improved antioxidant status as well as BLC-induced lung pathological changes, while it decreased the TNF-α, TGF-β (thus an anti-TGF-beta agent, thus claim 12 is met), IL-6, periostin, YKL-40, lipid peroxidation and collagen deposition. Finally, histological, immunohistochemical, and TUNNEL evidence also supported the ability of IFX to prevent BLC-induced lung fibrosis. The results of the present study indicate that IFX pretreatment can attenuate BLC-induced pulmonary fibrosis (see Abstract).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to advance from in vivo rat study to human clinical trial and use human as a subject (thus claim 15 is met), as it is the conventional drug developmental process. Since intraperitoneal administration is not available for human subject, oral administration (thus claim 7 is met) is a reasonable alternative administration route to adopt. Since 20 mg/kg APO was given to rat in Kilic et al, for a 50 kg human, the drug amount would be 1g, which falls into the claimed 0.5g/day to 10 g/day (thus claim 10 is met).
It would also have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to incorporate additional anti-TGF-beta agent infliximab into the composition since Altintas teaches IFX pretreatment can attenuate BLC-induced pulmonary fibrosis. Since both of the references teach treating BLC-induced lung fibrosis in rats, one of the ordinary skill in the art would have been motivated to combine the teachings of the references together.
Regarding the claimed IC50 in claim 9 and administration frequency in claim 11, determining an appropriate IC50 and administration frequency is deemed merely a matter of judicious selection and routine optimization which is well within the purview of the skilled artisan. Generally speaking, when IC50 is lower, and the administration frequency is higher, the treatment duration is shorter.
From the teachings of the references, it is apparent that one of the ordinary skills in the art would have had a reasonable expectation of success in producing the claimed invention.
Thus, the invention as a whole is prima facie obvious over the references, especially in the absence of evidence to the contrary.
Claims 1-3, 5-15 are rejected under 35 U.S.C. 103(a) as being unpatentable over Ye et al as applied to claims 1-3, 5, 6, 8, and 12-14 above.
The teachings of Ye et al are set forth above and applied as before.
The teachings of Ye et al do not specifically teach oral administration, the claimed dosage, administration frequency, or a human subject.
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to advance from in vivo rat study to human clinical trial and use human as a subject (thus claim 15 is met), as it is the conventional drug developmental process. Since intraperitoneal administration is not available for human subject, oral administration (thus claim 7 is met) is a reasonable alternative administration route to adopt. Since 20 mg/kg Sal B was given to rat in Lee et al, for a 50 kg human, the drug amount would be 1g, which falls into the claimed 0.5g/day to 10 g/day (thus claim 10 is met).
Regarding the claimed IC50 in claim 9 and administration frequency in claim 11, determining an appropriate IC50 and administration frequency is deemed merely a matter of judicious selection and routine optimization which is well within the purview of the skilled artisan. Generally speaking, when IC50 is lower, and the administration frequency is higher, the treatment duration is shorter.
From the teachings of the references, it is apparent that one of the ordinary skills in the art would have had a reasonable expectation of success in producing the claimed invention.
Thus, the invention as a whole is prima facie obvious over the references, especially in the absence of evidence to the contrary.
Conclusion
No claim is allowed.
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/Qiuwen Mi/
Primary Examiner, Art Unit 1655