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 without traverse of SEQ ID NO: 27 (PTD), SEQ ID NO: 19 (FAD), SEQ ID NO: 6 (TRD) and lecithin (phospholipid dispersant) in the reply filed on 7/4/25 was previously acknowledged.
In the reply filed 1/20/26, Applicants cancelled claims 1-14 and added new claim 15-34.
Claims 30-34 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected group, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on ***.
Claims 15-29 read on the elected species and are under consideration.
Drawings
The drawings were received on 1/20/26. These drawings are acceptable.
Claim Objections-Withdrawn
The objections to claims 1, 11 and 12 are withdrawn due to cancelation of the claims.
Claim Rejections - Withdrawn
The rejection of claims 12-14 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating peritoneal fibrosis with TRP2 at a therapeutic dose of 500 micrograms/kg or TRP2+ soy lecithin at a therapeutic dose of 5 micrograms/kg, does not reasonably provide enablement for treating all fibrotic diseases with TRP2 is withdrawn due to cancelation of the claims.
The rejection of claims 2 and 13 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or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention is withdrawn due to cancelation of the claims.
The rejection of claims 2 and 13 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends is withdrawn due to cancelation of the claims.
The rejection of claims 1-14 under 35 U.S.C. 103 as being unpatentable over Kim et al. (US20080064065,cited on IDS) in view van Hoogevest (European Journal of Pharmaceutical Sciences 108 (2017) 1-12) is withdrawn due to cancelation of the claims.
The rejection of claims 1-14 on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 of U.S. Patent No. 8,268,590 in view of van Hoogevest (European Journal of Pharmaceutical Sciences 108 (2017) 1-12) is withdrawn due to cancelation of the claims.
Claim Rejections - 35 USC § 112
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 15-29 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 treating peritoneal fibrosis with TRP2 at a therapeutic dose of 500 micrograms/kg or TRP2 +soy lecithin at a therapeutic dose of 5 micrograms/kg , does not reasonably provide enablement for promoting tissue formation, growth, regeneration or suppressing fibrosis comprising a non-activated TRP comprising a PTD, TRD, FAD and a dispersant. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to the invention commensurate in scope with these claims.
As stated in MPEP 2164.01(a), “there are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue.”
The factors to be considered when determining whether a disclosure meets the enablement requirement of 35 USC 112, first paragraph, were described in In re Wands, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988) as:
1. the nature of the invention;
2. the breadth of the claims;
3. the state of the prior art;
4. the relative skill of those in the art;
5. the predictability or unpredictability of the art;
6. the amount of direction or guidance presented [by the inventor];
7. the presence or absence of working examples; and
8. the quantity of experimentation necessary [to make and/or use the invention.
(1) The Nature of the Invention and (2) The Breadth of the claims
Claims 15-29 are drawn to an aggregation inhibited composition for promoting tissue formation, growth or regeneration or for suppressing fibrosis.
The instant specification states [PGPUB0004]:
A non-activated polypeptide (TRP: tissue-regenerative polypeptide) is a material having a new mechanism capable of promoting formation or regeneration of tissues such as bone, cartilage, and the like, or preventing fibrosis and hardening of organs such as the kidneys, liver, lungs, heart, and the like…
The instant specification states [PGPUB0073]:
In the present invention, the fibrotic disease may include liver fibrosis, muscle fibrosis, lung fibrosis, kidney fibrosis, cardiac fibrosis, peritoneal fibrosis, various eye diseases caused by fibrosis, and the like. This fibrosis inhibitory effect may be applied to various cancers such as liver cancer, as well as chronic diseases.
The claims will be given its broadest reasonable interpretation. The applicable rule for interpreting the claims is that “each claim must be separately analyzed and given its broadest reasonable interpretation in light of and consistent with the written description.” See MPEP 2163(II)(1), citing In re Morris, 127 F.3d 1048, 1053-1054; 44 USPQ2d 1023, 1027 (Fed. Cir. 1997).
(3) The state of the prior art and(5) The predictability or unpredictability of the art
The instant application is enabling for treating peritoneal fibrosis with TRP2 at a therapeutic dose of 500 micrograms/kg or TRP2 + soy lecithin at a therapeutic dose of 5 micrograms/kg , does not reasonably provide enablement for promoting tissue formation, growth or regeneration or suppressing fibrosis with the aggregation inhibited composition of claim 15.
The art is not enabling for promoting tissue formation, growth or regeneration or suppressing fibrosis in general. The Mayo clinic (https://www.mayoclinic.org/diseases-conditions/pulmonary-fibrosis/diagnosis-treatment/drc-20353695 accessed 7/25/25) teaches the lung scarring and thickening that occurs in Idiopathic Pulmonary Fibrosis (IPF) cannot be repaired. The Mayo clinic teaches that no current treatment has proved effective in stopping the disease from getting worse over time.
The Merck Manual (https://www.msdmanuals.com/professional/hepatic-and-biliary-disorders/fibrosis-and-cirrhosis/cirrhosis accessed 7/25/25) teaches cirrhosis is a late stage of hepatic fibrosis. The Merck Manual teaches treatment is supportive care.
Therefore, the state of the art at the time of the application is that the etiology and treatment of fibrosis and fibrotic diseases is not well understood and therapy is challenging and complex. Adding to the complexity are the many different diseases encompassed by the term fibrosis.
It is noted that pharmaceutical and biological art is generally unpredictable, requiring each embodiment to be individually assessed for physiological activity. Furthermore, the claimed “fibrotic disease” are different diseases with distinct etiologies and pathologies. Importantly, it is known in the art that there is not a clear understanding of the origins and pathophysiology of many “fibrotic diseases”. Given this fact, historically the development of new drugs has been difficult and time-consuming.
Adding to the unpredictability is that many treatment options may show promise in animal models, but may fail to show therapeutic improvement in clinical trials. There is no absolute predictability, even in view of the high level of skill in the art.
Thus, for promoting tissue formation, growth or regeneration or suppressing fibrosis, the possibilities are vast. And it would be highly unpredictable given the art and the breadth of the claims to determine if the aggregation inhibited composition would have the claimed function.
(4) The relative skill of those in the art
MPEP 2141.03 states (in part)” A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton.” KSR International Co. v. Teleflex Inc., 127 S.Ct. 1727, 167 LEd2d 705, 82 USPQ2d 1385, 1397 (2007). “[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle.” Id. Office personnel may also take into account “the inferences and creative steps that a person of ordinary skill in the art would employ.” Id. At 1396, 82 USPQ2d at 1396. The “hypothetical person having ordinary skill in the art’ to which the claimed subject matter pertains would, of necessity have the capability of understanding the scientific and engineering principles applicable to the pertinent art.” Ex parte Hiyamizu, 10 USPQ2d 1393, 1394 (Bd. Pat. App. & Inter. 1988) (disagreeing with the examiner’s definition of one of ordinary skill in the art (i.e. a doctorate level engineer or scientist working at least 40 hours per week in semiconductor research or development), and finding that the hypothetical person is not definable by way of credentials, and that the evidence in the application did not support the conclusion that such a person would require a doctorate or equivalent knowledge in science or engineering). In the instant case, the skill in the art high with respect to physicians and scientists. The level of skill in the art (physicians and scientists) would be high.
(6) The amount of direction or guidance presented (by the inventor) and (7) The presence or absence of working examples
The applicant provided sufficient guidance or direction regarding the potential treatment of peritoneal fibrosis with TRP2 at a therapeutic dose of 500 micrograms/kg or TRP2 + soy lecithin at a therapeutic dose of 5 micrograms/kg. Applicants provide in vivo data disclosing TRP2 reducing peritoneal thickness at a therapeutic dose of 500 micrograms/kg and TRP2 + soy lecithin at a therapeutic dose of 5 micrograms/kg.
In contrast, the applicant provides little in way of direction or guidance regarding generally promoting tissue formation, growth, regeneration or suppressing fibrosis. There was no disclosure of treatment of other animal models of fibrosis. Importantly, Tables 6-8 disclose the doses below 500 micrograms/kg of TRP2 were not effective and doses under 5 micrograms/kg for TRP2 + soy lecithin were not effective.
(8) The quantity of experimentation necessary (to make and/or use the invention)
MPEP 2164.01(a) states, “A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, 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 without undue experimentation. In re Wright, 999 F.2d 1557,1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).” That conclusion is clearly justified here.
The instant breadth of the claim is broader than the disclosure and the specification, prior art or instant disclosure does not provide support for this.
In conclusion, the instant application is enabled for treating peritoneal fibrosis with TRP2 at a therapeutic dose of 500 micrograms/kg or TRP2 (SEQ ID NO: 28)+ soy lecithin at a therapeutic dose of 5 micrograms/kg.
Claims 15-29 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.
MPEP § 2163 states that 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, 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. 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.
Scope of the claimed genus
Claims 15-29 are drawn to an aggregation inhibited composition for promoting tissue formation, growth or regeneration or for suppressing fibrosis comprising a non-activated TRP comprising a PTD, TRD and FAD and a dispersant selected from the group consisting of lecithin, polyethoxylated castor oil, triglycerides and lysophophatidlcholines. The instant specification discloses [PGPUB0056]:
In the present invention, the TRD may be represented by an amino acid sequence selected from the group consisting of SEQ ID NOS: 1 to 13, but the TRD is not limited thereto, so long as it is a protein having activity that promotes tissue growth or formation in cells or induces tissue regeneration. Such TRD is exemplified by a polypeptide selected from the group consisting of BMPs, TGF-β superfamily, β-NGF (β-nerve growth factor), β-amyloid, ADAMs (a disintegrin and metalloproteinase-like), TNF-α, MMPs (matrix metalloproteinases), insulin-like growth factor-1 (IGF-1), hepatocyte growth factor, and Dickkopf.
The USPTO provides claim terms with broadest reasonable interpretation in light of the specification. The definition of TRD is broad and encompasses any protein having activity that promotes tissue growth or induces tissue regeneration.
Assessment of whether species are support in the original specification
One embodiment of the invention of claims were reduced to practice at the time of filing. Applicants disclosed SEQ ID NO: 28 comprising SEQ ID NO: 27 (PTD), SEQ ID NO: 19 (FAD) and SEQ ID NO: 6 (TRD). SEQ ID NO: 6 is full length BMP-7.
In addition, the complete structure of the following species was disclosed: SEQ ID NOs: 1-13.
There was no disclosure of other peptide sequences that were able to inhibit peritoneal fibrosis other than SEQ ID NO: 28. The dispersants tested include Cremophor, egg lecithin, soybean lecithin, LysoPC, Glyceryl trioleate, DOTAP, DSPE-PEG-Amine and soybean oil.
In summary, for these reasons, the skilled artisan would reasonably conclude that the inventor(s), at the time the application was filed, had possession of SEQ ID NO: 28 and Cremophor, egg lecithin, soybean lecithin, LysoPC, Glyceryl trioleate, DOTAP, DSPE-PEG-Amine at the time the invention was filed.
Assessment of whether disclosed species are representative of the claimed genus
MPEP § 2163 states that 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, the disclosure of SEQ ID NOs: 1-13 are not representative of the genus. The disclosure of the sequences are not representative of the entire genus encompassed by TRDs because the genus is large. Furthermore, the genus of dispersants is quite large encompassing any triglyceride and lecthin, while only a few species are tested.
Identifying characteristics and structure/function correlation
In the absence of a reduction to practice of a representative number of species, the written description requirement for a claimed genus may be satisfied 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. To meet this requirement in the instant case, the specification must describe the structural, physical and/or chemical properties of an TRD that leads to promoting tissue formation, growth, regeneration or suppressing fibrosis and dispersants that lead to aggregation inhibition.
This is an issue of written description. The specification does not make clear which proteins are in the genus and which are not because it does not describe the physical basis for the claimed activity. In other words, the specification does not describe which proteins to make.
In conclusion, for the reasons presented above, the skilled artisan would reasonably conclude that the inventors, at the time the application was filed had full possession of the non-activated tissue regenerative polypeptide of SEQ ID NO: 28, Cremophor, egg lecithin, soybean lecithin LysoPC, glyceryl trioleate, DOTAP and DSPE-PEG Anime.
Response to Arguments
Applicant's arguments filed 1/20/26 have been fully considered but they are not persuasive. Applicants argue that claim 27 recites SEQ ID NO: 28 and withdrawn claim 34 is drawn to treatment of peritoneal fibrosis.
This argument is not persuasive for the reasons presented above. The claims are not enabled for promoting tissue formation, growth or regeneration or for suppressing fibrosis with the non-activated TRP.
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.
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 14-29 are rejected under 35 U.S.C. 103 as being unpatentable over Kim et al. (US20080064065,cited on IDS) in view van Hoogevest (European Journal of Pharmaceutical Sciences 108 (2017) 1-12). . Kim et al. teach a non-activated tissue-regeneration polypeptides (TRPs) containing: (a) a protein transduction domain (PTD) making the polypeptides to permeate cell membranes without cell membrane receptors; (b) a furin activation domain (FAD) which has at least one proprotein convertase cleavage site and which can be cleaved by the proprotein convertase and can activate a non-activated tissue regeneration domain (TRD) in cells; and (c) a non-activated TRD which can be activated in vivo by the proprotein convertase cleavage of the FAD. Kim et al. teach in vivo activated proteins are designed to stimulate the growth or formation of tissues or to induce the regeneration of tissues (Abstract, [0002, 0014]), meeting the limitations of claim 15 (in part).
Kim et al. does not teach a dispersant. However, the teachings of van Hoogevest cures this deficiency.
van Hoogevest teaches the knowledge and experiences obtained with oral phospholipid excipients is increasing continuously (Abstract). van Hoogevest teaches that phospholipids are multifunctional, biodegradable and non-toxic and can be used in oral dosage forms (Abstract). van Hoogevest teaches natural phospholipids may be considered environmentally friendly and a viable alternative to synthetic phospholipids (abstract). van Hoogevest teach lecithin has the GRAS status at the FDA (p. 1, bottom of 1st col.). van Hoogevest teaches lecithin is isolated from egg yolk or soybean (p. 5, 1st col. para 4.). van Hoogevest teach marketed oral produced soybean phospholipids are exclusively used in many oral product, soybean lecithin is mentioned as a component (p. 5, 1st col. para 4.). van Hoogevest teaches that since phospholipids play a significant role in the food uptake mechanisms of the GI tract and these mechanisms could be translated into suitable dosage forms and corresponding drug delivery strategies. van Hoogevest teaches due to their diversity in physicochemical properties and lack of toxicity (natural) phospholipids can replace many alternative synthetic excipients and for the pharmaceutical industry this means that the use of natural phospholipids will increase the over-all sustainability balance of their products (p. 10, 1st col. para 8.).
With respect to claims 15, 16 and 23, it would have been obvious to a person of ordinary skill in the art to include a dispersant such as soy or egg lecithin in the formulation of Kim et al. because van Hoogevest teaches due to their diversity in physicochemical properties and lack of toxicity (natural) phospholipids can replace many alternative synthetic excipients and for the pharmaceutical industry this means that the use of natural phospholipids will increase the over-all sustainability balance of their product. A person of ordinary skill would be motivated to include lecithin because van Hoogevest teaches that since phospholipids play a significant role in the food uptake mechanisms of the GI tract and these mechanisms could be translated into suitable dosage forms and corresponding drug delivery strategies. There is a reasonable expectation of success given that van Hoogevest teaches that phospholipids are multifunctional, biodegradable and non-toxic and can be used in oral dosage forms. Furthermore, phospholipids such as lecithin are routinely used in pharmaceutical formulations.
With respect to claim 17, Kim et al. teach the proprotein convertase is furin [0011, 0061, 0065, 0069, 0075].
With respect to claims 18-20, Kim et al. teach the TRD is SEQ ID NO: 6, which is BMP-7 [0069, 0114]. SEQ ID NO: 6 from Kim et al. is identical to instantly claimed SEQ ID NO: 6 (elected species).
With respect to claim 21, Kim et al. teach the FAD is SEQ ID NO: 19. Kim et al. teach the base sequence comprising hBMP7(SEQ ID NO: 6) with the FAD (SEQ ID NO: 19). SEQ ID NO: 19 from Kim et al. is identical to instantly claimed SEQ ID NO: 19 (elected species).
With respect to claims 22 and 26, Kim et al. teach the PTD is tat (SEQ ID NO: 27), which is identical to tat of the instant specification (SEQ ID NO: 27)(elected species).
With respect to claims 24 and 25, van Hoogevest teaches formulations of herbal medicine and phospholipid around 1:1. It is claimed that this 1:1 weight ratio is adequate to give rise to an increase of oral absorption compared to a comparator formulation (p. 7, 2nd col. para 6.2). The ratio of the dispersant and active ingredient is a result-effective variable and the determination of the optimum or workable ranges of said variable maybe characterized by routine experimentation (Please see MPEP 2144 II-Optimization of Ranges). It would have been obvious and routine experimentation to a person of ordinary skill in the art with a reasonable expectation of success to optimize the ratio to arrive at the ranges of claims 24 and 25.
With respect to claims 27-28, SEQ ID NO: 28 comprises SEQ ID NO: 6, 19 and 27 with an HA tag, histidine tag and X-press tag. Kim et al. teach the FAD is SEQ ID NO: 19. Kim et al. teach the base sequence comprising hBMP7(SEQ ID NO: 6) with the FAD (SEQ ID NO: 19). SEQ ID NO: 19 from Kim et al. is identical to instantly claimed SEQ ID NO: 19 (elected species).Kim et al teach tat as the PTD (SEQ ID NO: 27). Kim et al. also teach the recombinant vector was first prepared by inserting the base sequence of a BMP pro-domain having a furin cleavage site and the base sequence of PTD in front of the 5′ region of a BMP gene, and inserting in front thereof a base sequence for tagging, at least four histidine-encoding base sequences for separation and purification, and ATG as an initiation base sequence [0068]. Kim et al. also teach an X-press tag, six histidine encoding base sequences for separation and purification and an initiation base sequence were inserted [0090]. Kim et al. teach an HA tag may be used [0070]. It would have been obvious to a person of ordinary skill in the art to include the components of Kim et al. such as HA tag, X-press tag, histidine tag with SEQ ID NO: 6, 19 and 27 in order to create TRP2 (SEQ ID NO: 28) because Kim et al. teach the components for separation and purification. There is a reasonable expectation of success given the components are routine in recombinant technology and are routinely used. Moreover, the base sequence is known and taught by Kim et al.
With respect to the limitation of “dispersant”, it would have been obvious to a person of ordinary skill in the art to include a phospholipid dispersant such as soy or egg lecithin in the formulation of Kim et al. because van Hoogevest teaches due to their diversity in physicochemical properties and lack of toxicity (natural) phospholipids can replace many alternative synthetic excipients and for the pharmaceutical industry this means that the use of natural phospholipids will increase the over-all sustainability balance of their product. A person of ordinary skill would be motivated to include lecithin because van Hoogevest teaches that since phospholipids play a significant role in the food uptake mechanisms of the GI tract and these mechanisms could be translated into suitable dosage forms and corresponding drug delivery strategies. There is a reasonable expectation of success given that van Hoogevest teaches that phospholipids are multifunctional, biodegradable and non-toxic and can be used in oral dosage forms. Furthermore, phospholipids such as lecithin are routinely used in pharmaceutical formulations.
With respect to claim 29, Kim et al. teach the pharmaceutical formulation comprising a pharmaceutically acceptable excipient [0081].
Response to Arguments
Applicant's arguments filed 1/20/26 have been fully considered but they are not persuasive. Applicants argue that Kim fails to disclose a dispersant and van Hoogesvest fails to suggest inhibiting aggregation of a non-activated TRP. Applicants argue that van Hoogesvest does not mention a composition for promoting tissue formation, growth or regeneration or for suppressing fibrosis. Applicants argue that TRP particles typically exceed 300 micrometer in size due to aggregation. Applicants argue that Tables 1 and 3 of Example 2 disclose dispersants such as sugars, amino acids etc. proved ineffective in inhibiting aggregation inhibition of TRP2. Applicants argue that Example 3 measure the aggregation inhibitory impact of TRP2 employing 8 different types of emulsifiers, revealing that not all of the emulsifiers possessed aggregation inhibitory properties. Among these lecithin, polyethoxylated castor oil (Cremophor), triglycerides and lysophosphatidlcholines exhibited strong aggregation inhibitor effects (Table 4 of Ex. 3). Applicants argue that the instant application is the first to establish the use of lecithin, polyethoxylated castor oil (Cremophor), triglycerides and lysophosphatidlcholines as dispersants which significantly enhance the cell membrane permeability of TRP by reducing particle size due to the aggregation inhibitory effect of the TRP2 composition, all while remaining non-toxic. Applicants further argue that mitigating aggregation results in enhanced stability (Ex. 7).
These arguments were considered but are not persuasive. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In addition, dispersants such as lecithins are commonly used in pharmaceuticals. As disclosed above, it would have been obvious to a person of ordinary skill in the art to include a dispersant such as soy or egg lecithin in the formulation of Kim et al. because van Hoogevest teaches due to their diversity in physicochemical properties and lack of toxicity (natural) phospholipids can replace many alternative synthetic excipients and for the pharmaceutical industry this means that the use of natural phospholipids will increase the over-all sustainability balance of their product. A person of ordinary skill would be motivated to include lecithin because van Hoogevest teaches that since phospholipids play a significant role in the food uptake mechanisms of the GI tract and these mechanisms could be translated into suitable dosage forms and corresponding drug delivery strategies. There is a reasonable expectation of success given that van Hoogevest teaches that phospholipids are multifunctional, biodegradable and non-toxic and can be used in oral dosage forms. Furthermore, phospholipids such as lecithin are routinely used in pharmaceutical formulations and are known in the art to improve stability of the product. With respect to the arguments of unexpected results, the results are not commensurate in scope with the claims. The TRP tested was a specific fusion protein of SEQ ID NO: 28 and specific dispersants, while the composition of claim 15 is extremely broad encompassing a large genus of proteins and dispersants. Please see MPEP 2145. Furthermore, Table 4 also discloses the aggregation effect of DOTAP. However, DOTAP does not fall within the claimed Markush of dispersants. Therefore, the effect is not special to the claimed group of dispersants because it occurs in other structurally distinct dispersants.
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 15-29 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 of U.S. Patent No. 8,268,590 in view of van Hoogevest (European Journal of Pharmaceutical Sciences 108 (2017) 1-12). The USPN claims a method of preparing a non-activated TRP (claim 1). The non-activated TRP comprises a PTD-FAD-TRD. The FAD is a furin activation domain, The PTD is a protein transduction domain, wherein the PTD is TAT and the TRD is a tissue regeneration domain (claims 1-5). The USPN Kim et al. teach the TRD is SEQ ID NO: 6, which is BMP-7 [0069, 0114]. SEQ ID NO: 6 from Kim et al. is identical to instantly claimed SEQ ID NO: 6 (elected species). The USPN claims the FAD is SEQ ID NO: 19 and the TRD is SEQ ID NO: 6. SEQ ID NO: 19 and SEQ ID NO: 6 from the USPN is identical to instantly claimed SEQ ID NO: 19 and 6 (elected species). The USPN claims the PTD is tat (SEQ ID NO: 27), which is identical to instantly claimed SEQ ID NO: 27. The USPN claims a base sequence for tagging, at least four histidine base sequences for separation and purification (claims 1-5), which would meet the limitations of SEQ ID NO: 28. The USPN does not claim a dispersant. However, the teachings of van Hoogevest cures this deficiency.
van Hoogevest teaches the knowledge and experiences obtained with oral phospholipid excipients is increasing continuously (Abstract). van Hoogevest teaches that phospholipids are multifunctional, biodegradable and non-toxic and can be used in oral dosage forms (Abstract). van Hoogevest teaches natural phospholipids may be considered environmentally friendly and a viable alternative to synthetic phospholipids (abstract). van Hoogevest teach lecithin has the GRAS status at the FDA (p. 1, bottom of 1st col.). van Hoogevest lecithin is isolated from egg yolk or soybean (p. 5, 1st col. para 4.). van Hoogevest teach marketed oral produced soybean phospholipids are exclusively used in many oral product, soybean lecithin is mentioned as a component (p. 5, 1st col. para 4.). van Hoogevest teaches that since phospholipids play a significant role in the food uptake mechanisms of the GI tract and these mechanisms could be translated into suitable dosage forms and corresponding drug delivery strategies. van Hoogevest teaches due to their diversity in physicochemical properties and lack of toxicity (natural) phospholipids can replace many alternative synthetic excipients and for the pharmaceutical industry this means that the use of natural phospholipids will increase the over-all sustainability balance of their products (p. 10, 1st col. para 8.).
With respect to claims 15-29, it would have been obvious to a person of ordinary skill in the art to include a dispersant such as soy or egg lecithin in the formulation of the USPN. because van Hoogevest teaches due to their diversity in physicochemical properties and lack of toxicity (natural) phospholipids can replace many alternative synthetic excipients and for the pharmaceutical industry this means that the use of natural phospholipids will increase the over-all sustainability balance of their product. A person of ordinary skill would be motivated to include lecithin because van Hoogevest teaches that since phospholipids play a significant role in the food uptake mechanisms of the GI tract and these mechanisms could be translated into suitable dosage forms and corresponding drug delivery strategies. There is a reasonable expectation of success given that van Hoogevest teaches that phospholipids are multifunctional, biodegradable and non-toxic and can be used in oral dosage forms. Furthermore, phospholipids such as lecithin are routinely used in pharmaceutical formulations.
With respect the ratio, van Hoogevest to teaches formulations of herbal medicine and phospholipid around 1:1. It is claimed that this 1:1 weight ratio is adequate to give rise to an increase of oral absorption compared to a comparator formulation (p. 7, 2nd col. para 6.2). The ratio of the dispersant and active ingredient is a result-effective variable and the determination of the optimum or workable ranges of said variable maybe characterized by routine experimentation (Please see MPEP 2144 II-Optimization of Ranges). It would have been obvious and routine experimentation to a person of ordinary skill in the art with a reasonable expectation of success to optimize the ratio to arrive at the ranges instantly claimed.
Response to Arguments
Applicant's arguments filed 1/20/26 have been fully considered but they are not persuasive. Applicants point to the deficiencies of van Hoohesvest as recited in the remarks to the 103 rejection. Applicants request the ODP rejection be withdrawn.
This arguments was not persuasive for the reasons presented in the response to arguments section of the 103 rejection above.
Conclusion
No claims are allowed.
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/TARA L MARTINEZ/Examiner, Art Unit 1654
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