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 delayed graft function (renal disorder), SEQ ID NO: 1, IV administration and two doses in the reply filed on 6/11/25 was previously acknowledged.
In the reply filed 1/30/26, Applicants amended claims 1-4, 6-7, 11 and 24-25. Claim 14 was canceled and claim 26 is newly added.
Claims 1-13, 15-18 and 23-26 are pending.
Claims 1-13, 15-18 and 23-26 read on the elected species and are under consideration.
Claim Rejections - Withdrawn
The rejection of claim 2 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or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention is withdrawn due to amendment of the claim.
The rejection of claims 1-4, 9-10,12-13,18 and 25 under 35 U.S.C. 103 as being unpatentable over Keshavjee et al. (US20030180301) is withdrawn due to amendment of the claims.
Claim Rejections - 35 USC § 112-Maintained and Modified
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.
The rejection of claims 1-13, 15-18 and 23-25 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for therapeutic treatment of hypoxia and ischemic induced renal injury with Fetuin A (SEQ ID NO: 1), including renal ischemia or hypoxia during kidney transplantation, does not reasonably provide enablement for therapeutic treatment, prevention, reducing the risk of or delaying the onset of all renal disorders caused by renal hypoxia or ischemia with at least two doses of Fetuin A or functional fragments thereof is maintained and extended to new claim 26. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims. Please note that this rejection has been modified as necessitated by amendment of the 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
Claim 1 is drawn a method for treating, reducing the risk of or delaying the onset of a renal disorder caused by renal hypoxia and/or ischemia with at least two doses of Fetuin A or functional fragments thereof.
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). The instant specification defines treatment to include therapeutic treatment and prevention [PGPUB0021]. The instant specification defines “renal disorder” as one or more disorders or diseases affecting the kidney and encompasses renal injury not caused by disease [PGPUB0012]. In view of this rule, Claim 1 is drawn to therapeutic treatment, prevention, reducing the risk of or delaying the onset of all renal disorders caused by renal hypoxia and/or ischemia with Fetuin A or functional fragment thereof. Therefore, the claims encompass a broad genus of renal diseases in which hypoxia and/or ischemia is implicated.
(3) The state of the prior art and (5) The predictability or unpredictability of the art
The instant application is enabled for the therapeutic treatment of hypoxia and ischemic induced renal injury with Fetuin A (SEQ ID NO: 1) including renal ischemia or hypoxia during kidney transplantation. However, the limitation of “renal disorders” encompasses many different disorders with different etiologies and pathologies.
The state of the art establishes that renal hypoxia is a common physiological and pathological feature across many renal diseases including acute kidney injury, chronic kidney disease, diabetic nephropathy and others. Honda et al. (Kidney research and Clinical practice 2019;38(4) 414-426) teaches that the kidney is susceptible to hypoxia and renal hypoxia is a common final pathway to end stage kidney disease regardless of the underlying issue. The art also makes clear that the role of hypoxia varies across disease contexts, functioning in some cases a primary initiating factor (I/R injury) while in other cases as a secondary consequence of vascular or metabolic dysfunction or a as a downstream contributor to fibrosis and disease progression (Ow et al. Acta Physiologica Vol 222(4) 2018). The art silent regarding a single agent effective for preventing ,treating, reducing the risk of or delaying the onset of all renal disorders caused by hypoxia and/or ischemia.
Keshavjee et al. (see 103 rejection below) teach therapeutic treatment of a subject having received a kidney transplant with Fetuin A. Keshavjee et al. teach treatment of loss of transplant function such as medullary hypoxia which includes hypoxic tubular injury. Therefore, the art is also suggestive of therapeutic treatment of hypoxia and ischemic induced renal injury due to transplant with Fetuin A.
The state of the art at the time of the application is that the etiology and treatment of renal disorders is challenging and complex. Adding to the complexity are the many different diseases encompassed by the “renal disorders”. Therefore, treatment of “renal disorders” is complex and the art is silent for the treatment and prevention of all renal disorders caused by hypoxia and/or ischemia with a single compound.
It is noted that pharmaceutical and biological art is generally unpredictable, requiring each embodiment to be individually assessed for physiological activity. Furthermore, the claimed “renal disorders” are different diseases/disorders with distinct etiologies and pathologies. 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.
(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 therapeutic treatment of hypoxia induced renal injury with Fetuin A (SEQ ID NO: 1). Applicants provide in vitro and in vivo data supporting therapeutic treatment of hypoxic damage to kidneys. The data shows that administration of Fetuin A reduces the expression of known fibrosis markers in kidneys after I/R injury and the tissue shows less tissue damage and reduced fibrotic remodeling.
In contrast, the applicant provides little in way of direction or guidance regarding therapeutically treating, preventing, reducing the risk of or delaying the onset of other renal disorders caused by renal hypoxia and/or ischemia. There were no examples of treatment or prevention of CKD, renal inflammation, renal insufficiency etc. There was no indication that Fetuin A could prevent renal disorders. There was no indication that Fetuin A could prevent a renal disorder caused by hypoxia or ischemia during a kidney transplantation or cardiovascular surgery.
(8) The quantity of experimentation necessary (to make and/or use the invention)
Owing to the factors listed above, especially in points 6 and 7, the amount of experimentation needed will be extensive in view of the lack of guidance by the inventor. 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.
Response to Arguments
Applicant's arguments filed 1/30/26 have been fully considered but they are not persuasive. Applicants argue that the claims were amended to recite “treating, reducing the risk of or delaying onset of a renal disorder caused by hypoxia and/or ischemia” and “comprising the amino acid sequence of SEQ ID NO: 1, an amino acid sequence with at least 95% sequence identity to SEQ ID NO: 1 or a functionally active fragment thereof having Fetuin A activity”. Applicants argue that the specification explains that ischemia or ischemic refers to an inadequate blood supply to an organ or specific part of the body while hypoxia refers to a period of reduced oxygen supply. Applicants argue that the working examples provide detailed data and analysis in well-established model systems showing that administration of Fetuin A can be used a therapeutic treatment in these disorders. Applicants argue that the specification also provides support for reducing the risk of or delaying the onset of the claimed disorders. Applicants argue that Fetuin A was injected intravenously at various times before a surgery and was found to alleviate tissue damage. The pretreatment also reduced expression of certain chemokines involved in tissue damage. Applicants argue that PHOSITA would have understood how to obtain without undue experimentation the Fetuin A as recited in claims 1 and 25. Applicants argue that the structure of Fetuin A is well known in the art having 3 main domains and may be processed from a precursor into a mature protein consisting of the A and B chains. Applicants argue that PHOSITA would not only understand which domain of Fetuin A provide activity and which residues of SEQ ID NO: 1 could tolerate substitution, deletion or insertion.
These arguments were considered but are not persuasive. The Examiner agrees that the specification is enabled for the therapeutic treatment of hypoxia and ischemic induced renal injury with Fetuin A (SEQ ID NO: 1), including renal ischemia or hypoxia during kidney transplantation, but does not reasonably provide enablement for therapeutic treatment, prevention, reducing the risk of or delaying the onset of all renal disorders caused by renal hypoxia or ischemia with at least two doses of Fetuin A or functional fragments thereof. The claims are broader and the specification does not reasonably provide enablement for preventing, delaying the onset of or reducing the risk of all renal disorders caused by hypoxia and/or ischemia. The breadth of the claims is further expanded by the inclusion of functional fragments of Fetuin A. The specification does not provide sufficient guidance to enable the full scope of the claims. Determining which fragments retain the claimed therapeutic activity across the full scope of the claims would require substantial screening and experimentation. Therefore, in view of the breadth of the claims, the limited guidance provided in the specification, undue experimentation would be required to practice the full scope of the claimed invention.
Claim Rejections - 35 USC § 112-Maintained
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.
The rejection of claims 1-13, 15-18 and 23-25 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 is maintained and extended to new claim 26. This rejection has been modified necessitated by amendment of the claims.
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
Claim 1 is drawn a method for treating, reducing the risk of or delaying the onset of a renal disorder caused by renal hypoxia and/or ischemia with at least two doses of Fetuin A or functional fragments thereof.
The USPTO provides claim terms with broadest reasonable interpretation in light of the specification. The instant specification defines treatment to include therapeutic treatment and prevention [PGPUB0021]. The instant specification defines “Fetuin A” to include a protein or fragments thereof or derivative thereof which are naturally occurring or non-naturally occurring but has the same or similar functions as naturally occurring Fetuin A [PGPUB0032]. The instant specification also encompasses all naturally occurring alleles, splice variants and isoforms as well as synthetic peptides, peptide mimetics or peptide fragments [PGPUB0032]. The instant specification states that “fragments” can be at least 20% the length of SEQ ID No: 1 and may comprise additional amino acids that are part of or not part of the full length SEQ ID NO: 1 [0036]. Therefore, “Fetuin A” as recited in the claims includes full length Fetuin A, fragments, variants and derivatives thereof.
Assessment of whether species are support in the original specification
The instant specification provides SEQ ID NO: 1 (human Fetuin A) and SEQ ID NO: 3 (bovine Fetuin A).
There was no disclosure of fragments, variants and derivatives for treating renal disorders. SEQ ID NO: 1 (human) was injected for the experiments.
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: 1 and 3 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 NO: 1 and 3 are not representative of the genus of functionally active fragments of fetuin A. The disclosure of the sequences are not representative of the entire genus encompassed by fragments, variants and derivatives of Fetuin A.
With the aid of a computer, one of ordinary skill in the art could identify all of the peptides fragments of Fetuin A, however there is no teaching which fragments would have the claimed function.
Therefore, disclosure of SEQ ID NO: 1 and 3 are not representative of the genus.
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 Fetuin A that leads to the claimed function of treating and preventing renal disorders.
The data do not suggest the physical basis for the claimed activity and therefore do not describe which substitutions, deletions or additions could be made while preserving function. Understanding the physical basis for the claimed activity is critical to determining which of the sequences that meet the structural requirements of the genus also meet the functional requirements of the genus. This is an issue of written description. The specification does not make clear which proteins/peptides 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 SEQ ID NO: 1, SEQ ID NO: 3 and an amino acid sequence with at least 95% sequence identity to SEQ ID NO: 1.
Response to Arguments
Applicant's arguments filed 1/30/26 have been fully considered but they are not persuasive. Applicants argue that one of ordinary skill in the art would have understood the specification to clearly disclose functionally active fragments of Fetuin A. Applicants further argue that it is within one of ordinary skill in the art to obtain functionally active fragments and the knowledge and expertise of one of ordinary sill in the art given that Fetuin A is a well understood human protein. Applicants argue that a disclosure need not include and preferably omit such well known information.
This argument was considered but is not persuasive because the written description requirement is not satisfied because methods of generating protein fragments are known in the art or because the protein is a well-known protein. The specification fails to reasonably convey to one of ordinary skill in the art that Applicants had possession of the claimed genus of functional fragments. Although the specification describes full length human fetuin A and demonstrates some therapeutic activity for the full length protein, the specification does not adequately describe which fragments are encompassed by the claims. Furthermore, the specification does not provide sufficient representation of fragments or disclose a correlation between structure and function such that one of ordinary skill in the art would conclude that the Applicants had possession of the genus. For the reasons presented above, the rejection is maintained.
Claim Rejections - 35 USC § 103-Maintained and Modified
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.
The rejection of claims 1-13, 15-18 and 23-25 under 35 U.S.C. 103 as being unpatentable over Keshavjee et al. (US20030180301) in view of Tracey et al. (USPN 7,186,555) is maintained and extended to new claim 26. Please note this rejection has been modified necessitated by amendment of the claims.
Keshavjee et al. teach the use of TGF-β antagonist to treat loss of transplant organ function (Abstract). Keshavjee et al. teach and claim the transplant organ is a kidney (claims 4, 23 and [0013,0022, 0023, 0025]. Keshavjee et al. teach loss of transplant function refers to physiological disruption or dysfunction of the normal process of the organ. For example, in a kidney transplant, diminution of pressure filtration, selective reabsorption, or tubular secretion indicate loss of kidney function, as do medullary hypoperfusion; medullary hypoxia, including hypoxic tubular injury, tubular necrosis, formation of protein casts and tubular obstruction, or other manifestations that reduce tubular flow; as well as manifestations that reduce medullary blood flow such as ischemia and other vasa recta injury [0027]. Keshavjee et al. teach and claim the TGF-β antagonist is Fetuin (claims 13, 32 [0017,0036]). Keshavjee et al. teach that TGF-β plays a significant role in chronic rejection of transplanted organs and teach TGF-β antagonist act as effective therapeutics [0013].
Keshavjee et al. does not teach an example of treating a renal disorder caused by hypoxia and/or ischemia in a subject, however the teachings of Keshavjee et al. is suggestive of the limitation.
With respect to claims 1 and 25, It would have been obvious before the effective filing date of the invention to use fetuin A for treatment of a renal disorder, such as hypoxic injury due to transplantation as taught by Keshavjee et al. A person of ordinary skill in the art would look to the teachings of Keshavjee et al. and have a motivation to use Fetuin because Keshavjee et al. teach complications in kidney transplantations include medullary hypoperfusion and medullary hypoxia can be treated with a TGF-β antagonist such as Fetuin. There is a reasonable expectation of success given that Keshavjee et al. teach that TGF-β plays a role in the rejection of organs such as the kidney and a TGF-β antagonist, such as Fetuin can be administered as an effective therapeutic to prevent loss of the transplant function.
Keshavjee et al. does not teach the sequence of fetuin, the dose and treatment regimen. However, the teachings of Tracey et al. cure this deficiency.
Tracey et al. teach inhibiting tissue damage caused by ischemia by administering human ASHG (Fetuin), wherein the ASHG is SEQ ID NO: 1. SEQ ID NO: 1 from Tracey et al. is 98.8% identical to instantly claimed SEQ ID NO: 1, meeting the limitation of “comprises an amino acid sequence with at least 95% identity to SEQ ID NO: 1”. Tracey teaches that AHSG is the human homolog of fetuin (col. 1, lines 49-51). Tracey et al. teach experiments wherein brain damage subsequent to focal ischemia was found to be ameliorated by treatment with AHSG (col. 3, lines 11-14). Tracey et al. teach other organs and tissues may become afflicted by ischemia and any of these conditions of ischemia and their clinical relations is amenable to treatment according to the methods and pharmaceutical conditions of the invention (col. 3, lines 50-58).
With respect to the new limitation in claim 1 “at least two doses of an effective amount of Fetuin A”, and the limitation of claims 15-17 and 24, Tracey et al. teach the goal of the method is to prevent the loss of viable brain tissue in the early hours after the onset of ischemia (col. 1, 3rd para.). Fig. 2 discloses administration of AHSG 15 mins after induction of ischemia. Fig. 4 discloses administration of ASHG intravenously 15, 30 or 60 after ischemia induction. Tracey et al. teach the final determination of the “therapeutic window” during the AHSH therapy is effective for specific clinical conditions is readily accomplished by those skilled in the medical and pharmaceutical arts (col. 7, 1st para.). It would be obvious to a person of ordinary skill in the art to optimize the treatment regimen for the treatment of a renal disorder, such as hypoxic injury due to transplantation as taught by Keshavjee et al. The timing of administration and dosing schedule 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). In the instant case, Tracey et al. teach Fig. 2 discloses administration of AHSG 15 mins after induction of ischemia. Fig. 4 discloses administration of ASHG intravenously 15, 30 or 60 after ischemia induction. 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 timing of administration and dosing schedule, to arrive at the limitations of claims 1, 15-17 and 24.
With respect to claims 2, 3 and 4, the teachings of Keshavjee et al. meet the limitations of a subject has received a kidney transplantation and kidney tissue damage, delayed graft function and renal disorder caused by hypoxia during surgery including during kidney transplantation.
With respect to claims 5-6 and 23, Tracey et al. teach and claim the AHSG is SEQ ID NO: 1 (col. 3, 1st para.). SEQ ID NO: 1 of Tracey et al. meets the limitations of human Fetuin A, at least 95% sequence identity to SEQ ID NO: 1. SEQ ID NO: 1 from Tracey et al. is 98.8% identical to instantly claimed SEQ ID NO: 1. Tracey et al. teach AHSG is a human plasma glycoprotein (col. 4, lines 38-40) and AHSG was first isolated from bovine serum and are found in human plasma (col. 2, 2nd para.). AHSG is found in fetal plasma at high concentrations (col. 1, lines 55-56).
With respect to claim 7, It would have been obvious to optimize the sequence of fetuin for the treatment of a renal disorder, such as hypoxic injury due to transplantation as taught by Keshavjee et al. A person would look to the teachings of Tracey et al. that teaches the sequence of fetuin and specific fragments thereof for treating ischemic injury to the brain and other organs and have a motivation to use the sequences for treating hypoxic and ischemic injury in the kidney. There is a reasonable expectation of success given that the sequence of human fetuin is well known in the art and exemplified in Tracey et al. Furthermore, MPEP 2144.05 states obviousness of similar and overlapping ranges, amounts and proportions. In particular, MPEP 2144.05 states: a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v.Banner, 778 F.2d 775, 783,227 USPQ 773, 779 (Fed. Cir. 1985) (Court held as proper a rejection of a claim directed to an alloy of “having 0.8% nickel, 0.3% molybdenum, up to 0.1% iron, balance titanium” as obvious over a reference disclosing alloys of 0.75% nickel, 0.25% molybdenum, balance titanium and 0.94% nickel, 0.31% molybdenum, balance titanium. “The proportions are so close that prima facie one skilled in the art would have expected them to have the same properties.”). In the instant case, the Tracey et al. teach a sequence of Fetuin A that is 98.8% identical to instantly claimed SEQ ID NO: 1. There is a reasonable expectation of success given the great similarity between sequences having 98.8% and 100% identity to SEQ ID NO: 1, one of ordinary skill in the art would reasonably conclude that the sequences have similar properties.
With respect to claim 8, Tracey et al. teach that the glycoproteins are conveniently produced according to techniques of molecular biology well known in the art and readily compared to human AHSH (col. 3, lines 24-30), meeting the limitation of recombinant.
With respect to claims 9 and 10, Keshavjee et al. teach intravenous administration and intramedullary [0031]. Tracey et al. teach intravenous administration of AHSG (Fig. 4, top of col. 5, Ex. 2 and 4).
With respect to claim 11, Tracey et al. teach intravenous administration of 5 mg/kg, 25 mg/kg, 50 mg/kg, 500 mg/kg (Fig. 3, 4, Ex. 2-4). The MPEP 2144.05 (Obviousness of Ranges) states: “In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists.” In reWertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976)
With respect to claims 12-13, With respect to the limitation “wherein the treatment modulates calcification levels in the kidney” and “removes calcium mineral depositions in kidney tissue”, the composition comprising an effective amount of Fetuin from Keshavjee et al. would inherently have all of the activities and properties of the composition of claim 1. The MPEP § 2112 states: “Once a reference teaching product appearing to be substantially identical is made the basis of a rejection, and the Examiner presents evidence or reasoning tending to show inherency, the burden shifts to the Applicant to show an unobvious difference ‘[t]he PTO can require an Applicant to prove that the prior art products do not necessarily or inherently possess the characteristics of his [or her] claimed product. Whether the rejection is based on inherency’ under 35 U.S.C. 102, on prima facie obviousness’ under 35 U.S.C. 103, jointly or alternatively, the burden of proof is the same…[footnote omitted].” The burden of proof is similar to that required with respect to product-by-process claims. In re Fitzqerald, 619 F.2d 67, 70, 205 USPQ 594, 596 (CCPA 1980) (quoting In re Best, 562 F.2d 1252, 1255, 195 USPQ 430,433- 34 (CCPA 1977)).” In other words, Keshavjee et al. make obvious administering the same composition (effective amount of fetuin) to the same patient population (a subject with renal disorder), therefore the compound would have the same properties. Moreover, MPEP 2112.01 states: “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.
With respect to claim 18, Keshavjee et al. teach the pharmaceutical composition refers to any composition that contains a pharmaceutically effective amount of the TGF-β antagonist with one or more pharmaceutical carriers or additives [0029].
With respect to new claim 26, Keshavjee et al. teach treatment or delaying transplant rejection of heart or kidney [0024], meeting the limitation of cardiovascular surgery.
Response to Arguments
Applicant's arguments filed 1/30/26 have been fully considered but they are not persuasive. Applicants argue that Keshavjee does not teach the claimed sequence of Fetuin A nor does Keshavjee teach that Fetuin A could be successfully used for treating, reducing the risk of or delaying the onset of a renal disorder caused by hypoxia and/or ischemia, such that as due to transplantation or cardiac surgery, wherein at least 2 doses are required. Applicants argue that Keshavjee refers to generally using a TGF-beta antagonist in a transplant recipient, all the working examples are performed with TFGBIIIR which is an entirely different molecule with a different mechanism of action compared to Fetuin A. Applicants argue that the reference merely provides a laundry list of possible TGF-beta antagonist [0036] which includes everything from antibodies, proteins, proteoglycans and antisense oligonucleotides with no information on how to administer the agents. Therefore, the reference does not provide a reasonable expectation of success for the claimed method. Applicants argue that the Tracey reference does not cure the deficiencies of Keshavjee. Applicants argue that Tracey teaches administration of a single dose of Fetuin A and is drawn to treatment of stroke in the brain, not renal inflammation or tissue damage due to hypoxia and/or ischemia in the kidney. Applicants argue the Examiner does not suggest a link between the two disorders. Applicants argue that the PCT publication of Tracey states that elevated levels of Fetuin A increase the risk for myocardial infarction ad ischemic stroke showing the role of Fetuin A as a prophylactic agent is not fully understood (specification, p. 2). Application argue they pointed out that the art as a whole was uncertain as to whether Fetuin A would be helpful or harmful. Applicants argue that both references do not teach administering more than a single dose, while the instant specification show repeated injections in a murine I/R model were particularly beneficial. Applicants argue that administration before I/R reduced tissue damage and fibrotic remodeling such treatment reduced the risk of and/or delayed the onset of any tissue damage including fibrotic tissue damage and such results could not have been reasonably expected from the combination of Keshavjee and Tracey. Applicants further argue that the references do not teach or suggest the administration of Fetuin A could provide the additional benefits of claims 12-13. Applicants argue that the effects were not expected by the cited art.
These arguments were considered but are not persuasive as Keshavjee claims the use of Fetuin A (see claims 13 and 32) for inhibiting rejection of a kidney transplant (see claims 1 and 4). In claims 13 and 32, Fetuin A is recited in a total of 6 agents. Therefore, Fetuin A is not claimed in “a laundry list” of agents. With respect to the argument that the prior art does not teach working examples, MPEP 2121 states: When the reference relied on expressly anticipates or makes obvious all of the elements of the claimed invention, the reference is presumed to be operable. Once such a reference is found, the burden is on applicant to rebut the presumption of operability. With respect to the argument regarding the Tracey reference, 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 the instant case, Tracey is used to make obvious the sequence of fetuin, the dose and treatment regimen. As indicated above, the dose and treatment regimen is a result driven variable. Tracey et al. teach the final determination of the “therapeutic window” during the AHSH therapy is effective for specific clinical conditions is readily accomplished by those skilled in the medical and pharmaceutical arts (col. 7, 1st para.). It would be obvious to a person of ordinary skill in the art to optimize the treatment regimen for the treatment of a renal disorder, such as hypoxic injury due to transplantation as taught by Keshavjee et al. The timing of administration and dosing schedule 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). Importantly, repeated or multiple doses of a therapeutic agent is well known in the art. With respect to the statement that the PCT publication of Tracey states that elevated levels of Fetuin A increase the risk for myocardial infarction and ischemic stroke showing the role of Fetuin A as a prophylactic agent is not fully understood (specification, p. 2), such a statement further demonstrates the unpredictability of prophylactic application of Fetuin A as recited in the scope of enablement above. The additional benefits of claims 12-13 would inherently occur since the same compound is administered to the same patient population. For the reasons presented above, the rejection is maintained.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/TARA L MARTINEZ/Examiner, Art Unit 1654
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