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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 1/30/2026 has been entered.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Claims 1-20, and 22-23 have an effective filing date of 06 MAR 2019.
Election/Restriction
In the response filed on 12/19/2024, Applicant elected, with traverse:
Species
GRP78
The sense of SEQ ID NO:8 and antisense SEQ ID NO: 9
Obesity
Oral administration
Status of Claims
Claims 1-20, and 22-23 are currently pending.
Claims 2, 9, 18, 20, and 22-23 are withdrawn from further consideration by Examiner under 37 CFR 1.142(b) as being drawn to a non-elected species.
Claim 21 is canceled.
Claims 22-23 are new.
Claims 1 and 8 are amended.
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.
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 factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1, 3, 5-8, 10, 12-17, and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Baik et al (KR 20180110419 A), and further in view of Hatanaka et al (US 20180353434 A1).
Baik et al teaches GRP78 is associated with increased ER stress, it is known that insulin resistance plays an important role in maintaining energy metabolism and that GRP78 is a key regulator of energy metabolism, thus overexpression of GRP78 has been shown to increase obesity [2nd paragraph, pg. 2]. Baik et al further teaches a method for screening for an obesity-suppressing agent and treatment of obesity [Abstract]. Baik et al further teaches the obesity inhibitor is capable of binding to GRP78 [Abstract]. Baik et al further teaches treatment with the obesity-suppressing agent inhibits obesity [Abstract]. Baik et al further teaches the expression level of GRP78 was about 1.7 times in obese mice vs normal mice [Example 5, pg. 5]. Baik et al further teaches melanocortin 4 receptor (MC4R) binds GRP78, but when MC4R is mutated in humans, the obese trait is rapidly induced [Description, 3rd paragraph, pg. 1]. Baik et al further teaches heat shock chaperone 70 (HSC70) is known to stabilize MC4R and increase cell membrane expression [1st paragraph, pg. 2]. Baik et al further teaches a substance that increases the binding level of GRP78 and MC4R as an obesity inhibitor [8th paragraph, pg. 2]. Baik et al further teaches inhibition of GRP78 by PVN injection of Lentilox RNAi vector Lenti-shGRP78 [Fig. 8, pg. 2]. Baik et al further teaches the inhibitor of obesity can be formulated into oral formulations [19th paragraph, pg. 3]. Baik et al further teaches administering the oral composition in the form of a pharmaceutically acceptable carrier or with an excipient [3rd paragraph, pg. 4].
Applicant states in Table 0, on page 7 of the specifications that HSC70 is a synonym for HSP70-8/HSP71.
With regard to said inhibitors administered simultaneously or sequentially is clearly a result effective parameter that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ. It would have been customary for an artisan of ordinary skill to determine the parameters to achieve the desired results. Thus, absent some demonstration of unexpected results from the claimed parameters, the optimization of ingredient amounts would have been obvious at the time of applicant's invention.
The principle of law states from MPEP 2144.05: "The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages."(Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382); Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
Baik et al does not specifically teach lipid nanoparticles with said molecule of interfering RNA. However, this deficiency is made up in the teachings of Hatanaka et al.
Hatanaka et al teaches the use of nanoparticles to treat a subject [0367]. Hatanaka et al further teaches the introduction of lipid nanoparticles into mammalian cells in the intestine [0908]. Hatanaka et al further teaches the lipid nanoparticles using RNA interference [0909].
One of ordinary skill, before the effective filing date, would have been motivated to use Baik’s method of screening for obesity-suppressing agents that decrease free GRP78 for an oral treatment of the insulin dependent pathology obesity, with Hatanaka’s method of using oral lipid nanoparticles to deliver interfering RNA to the intestines, because both demonstrate treating cells using RNA interference. Furthermore, to administer the oral treatment simultaneously or sequentially. The idea of combining them flows logically from their having been individually taught in the prior art (MPEP 2144.06). Combining prior art elements according to known methods to yield predictable results is an exemplary rationale for a prima facie case of obviousness. MPEP2143. It would have been prima facie obvious to use Baik and Hatanaka’s method for screening for an obesity-suppressing agent that increases the binding of GRP78 to treat an insulin resistance and/or pathologies derived therefrom by delivering interfering RNA to the intestine, because both teach delivering interfering RNA orally to treat subjects.
Applicant’s Arguments:
Applicant respectfully traverses the rejection especially as it may be applied to the amended claims presented herein.
Applicant has amended the claims to clarify that the method comprises inhibition of secreted, extracellular or circulating GRP78.
Baik is fundamentally directed to intracellular GRP78 biology in the context of central nervous system regulation of energy homeostasis, including pathways involving MC4R, and it frames GRP78 in its conventional chaperone/ER-resident role and related neuronal mechanisms rather than as a secreted, extracellular circulating factor originating from the intestine. Baik focuses on GRP78 as an endoplasmic reticulum-resident chaperone protein that modulates melanocortin 4 receptor (MC4R) signaling within the central nervous system, particularly the paraventricular nucleus (PVN) of the hypothalamus.
Examiner’s Response:
Applicant states, “Baik focuses on GRP78 as an endoplasmic reticulum-resident chaperone protein that modulates melanocortin 4 receptor (MC4R) signaling within the central nervous system”.
Baik et al further teaches inhibition of GRP78 by PVN injection of Lentilox RNAi vector Lenti-shGRP78 [Fig. 8, pg. 2].
One of ordinary skill would recognize that Baik teaches the inhibition of GRP78 using siRNA. Furthermore, using the siRNA Baik inhibited all GRP78, to include secreted, extracellular, and circulating GRP78.
While the examples in Baik indeed use the GRP78 inhibitor on intracellular GRP78, a prior art reference is relevant for all its teachings, not only its examples. Merck & Co. v. Biocraft Labs., Inc., 874 F.2d 804, 807 (Fed. Cir. 1989) (holding that both preferred and unpreferred embodiments must be considered). In addition, Applicants point to narrow embodiments which are not the sum total of information conveyed by each. Art is art, not only for what it expressly teaches, but also for what it would reasonably suggest to the skilled artisan, including alternative or non-preferred embodiments. MPEP § 2123.
New Grounds of Rejection
35 U.S.C. 112(a) – Written Description
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 1, 3-8, 10-17, and 19 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims 1 and 8 are drawn to an inhibitor of GRP78 activity, wherein said inhibitor is an anti-GRP78 monoclonal antibody. The claims encompass a large genus of antibodies that are capable of inhibiting GRP78 activity. Following a review of the Specification, it appears that one inhibitor of GRP78 activity, wherein said inhibitor is an anti-GRP78 monoclonal antibody, has been described, specifically GRP78 monoclonal antibody C38, see p. 10; however in view of this disclosure, Applicant is claiming a broad genus of molecules that would be expected to encompass multiple antigen-binding domains having diverse heavy and light chain CDR sequences. Even though Applicant has disclosed one species within the claimed genera, the specification does not provide adequate written description for the entire claimed genera, because one skilled in the art would be unable to immediately envision, recognize, or distinguish at least most of the members comprised within the genera claimed, specifically, which light and heavy chain CDR sequences (and combinations of said CDR sequences) give rise to an anti-GRP78 antibody capable of inhibiting GRP78 activity. As detailed below Applicant’s disclosure is not sufficient to demonstrate possession of the entire claimed genus, and as such Applicant’s disclosure does not satisfy the written description requirement of 35 U.S.C. 112(a).
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
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A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. In the instant case, Applicant has disclosed one species within the genera claimed; however given the substantial antibody structure variation within the genera as well as the high level of unpredictability in the antibody arts, the disclosure provided by the specification is not sufficiently representative of the entire genera claimed.
It is further noted that the claims require an anti-GRP78 antibody that inhibits GRP78 activity. One skilled in the art would reason that while some anti-GRP78 antibodies are likely inhibitory, other anti-GRP78 antibodies will likely not be capable of inhibiting GRP78 activity. Applicant has not provided any general structure of an anti-GRP78 antibody that is capable of inhibiting GRP78 activity. This is a significant omission, because the ability of an antibody to bind a particular antigen, alone, does not characterize what other properties the antibody may or may not possess. It is well-recognized in the art that antibodies will display markedly different and unpredictable properties depending on the epitope in an antigen to which a particular antibody specifically binds. Stancovski et al. (PNAS, 88: 8691-8695, 1991) developed a panel of monoclonal antibodies specific to HER-2, an art-known tumor antigen, and Stancovski et al. discovered that although each antibody bound the HER-2 antigen, said antibodies displayed a range of different properties, see Abstract and p. 8694, Table 1. Two of the anti-HER-2 antibodies almost completely inhibited tumor growth, two anti-HER-2 antibodies displayed moderate inhibitory effects, and yet another anti-HER-2 antibody accelerated tumor growth, p. 8694, Table 1. Additionally, said panel of anti-HER-2 antibodies demonstrated a range of apparent affinities and a range of abilities to induce complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity, and tyrosine phosphorylation, p. 8694, Table 1, and p. 8692, second column, second full paragraph. Furthermore, similar to Stancovski et al., Jiang et al. (J. Biol. Chem., 280: 4656-4662, 2005) teach that while many anti-HER-2 antibodies inhibit the proliferation of cancer cells, other anti-HER-2 antibodies actively stimulate cancer growth, see p. 4656, second column, final paragraph. Importantly, Jiang et al. add that “[i]t is well known that different biological effects are associated with the epitope specificity of the antibodies.” See p. 4656, second column, final paragraph. Based upon the teachings of Stancovski et al. and Jiang et al., one skilled in the art would reason that antibodies specific for the same target protein may have different effects depending upon the epitope specificity of a particular target protein-specific antibody.
Although screening techniques can be used to isolate anti-GRP78 antibodies that are capable of inhibiting GRP78 activity, Applicant is reminded that the written description requirement of 35 U.S.C. 112 is severable from the enablement provision. As stated in Vas-Cath Inc. v. Mahurkar (CA FC) 19 USPQ2d 1111, 935 F2d 1555, “The purpose of the ‘written description’ requirement is broader than to merely explain how to ‘make and use’; the applicant must also convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.”
Accordingly given the lack of particularity with which the claimed antibodies are described in the specification, it is submitted that the skilled artisan could not immediately envision, recognize, or distinguish at least most of the members of the genus to which the claims are directed, and therefore the specification would not reasonably convey to the skilled artisan that Applicant was in possession of the claimed invention at the time the application was filed.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DENNIS JOHN SULLIVAN whose telephone number is (571)272-0509. The examiner can normally be reached Mon - Fri: 7:30AM - 4:30PM.
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/DENNIS J SULLIVAN/Examiner, Art Unit 1642
/NELSON B MOSELEY II/Primary Examiner, Art Unit 1642