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 .
Objections
Claim 2 is objected to, as the claims are likely intended to refer to “the composition,” not “composition.” Appropriate correction is required.
Restriction/Election
Applicant’s election without traverse of Group I, claims 1-4, 6, 8, 9, 11, 13, 15, 18, 22, 30, 35, 36, 42, 45 and 48 in the reply filed on 09/25/25 is acknowledged.
Claims 51 and 53 are withdrawn. Election was made without traverse in the reply filed on 09/25/25. Claims 1-4, 6, 8, 9, 11, 13, 15, 18, 22, 30, 35, 36, 42, 45 and 48 are under examination. Claim 36 was searched and found to be free of the art, as the specific composition claimed is not taught as an artificial blood substitute or extracorporeal priming fluid. The art appears to teach away from compositions comprising transferrin as a an artificial blood replacement. The remaining claims 1-4, 6, 8, 9, 11, 13, 15, 18, 22, 30, 35, 42, 45 and 48. An Office action on the merits follows.
Claim Rejections 35 USC 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 8 is rejected 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. Claim 8 states that the albumin of claim 6 may be polymeric or monomeric. Albumin can only be either one albumin monomer or multiple albumin monomers, as the only other option would be zero. As such, this does not further limit claim 6. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections 35 USC 103(a)
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.
Claim(s) 1-3, 6, 8, 9, 18, 22, 35, 42 and 48 are rejected under 35 U.S.C. 103 as being unpatentable over Cooper et al. (US2018/0353543; See ISR), in view of Powanda et al. ( Surgery, Obstetrics and Gynecology, Vol. 153, 749-755, 1981).
Cooper teaches methods for improving wound healing and reducing scar formation with protein compositions for such treatment that are derived from plasma and Cohn fraction IV and/or IV-1, which comprise transferrin, haptoglobin and immunoglobulins [0001; 0021]. This reference teaches that wounds are caused by a disruption in the structural integrity of biological tissue and that wound healing and the classic model of wound healing encompasses four sequential, yet overlapping, phases comprising hemostasis, inflammation, proliferation, and remodeling [0007]. Cooper teaches that during the inflammation phase, platelet aggregation and clotting form a matrix which traps plasma proteins and blood cells to induce the influx of various types of cells, during the cellular proliferation phase, new connective or granulation tissue and blood vessels are formed and in the remodeling phase, granulation tissue is replaced by a network of collagen and elastin fibers leading to the formation of scar tissue [0007]. Cooper further teaches that the wound healing activity can be attributed to the unique combination of plasma proteins and other compounds resulting from the process of Alpha-1 Antitrypsin (AAT) removal and that the small amount of AAT residing in the composition may shift the balance of protease/anti-protease activity to the favor of proteases, enabling removal of deleterious proteins and contributing to the wound healing process [0023]. In order to aid in wound repair, this reference teaches that mice were treated with a composition comprising 3.9% haptoglobin, 11% transferrin, 4.2% ceruplasmin and 2.1% albumin (Table 2; Example 2). The results showed that the composition was effective for aiding in wound healing in the initial stages of the healing process [0155].
The difference between the prior art and the instant claims is that the prior art does not explicitly teach that the composition is used for treating plasma protein imbalance with the claimed concentration of proteins.
However, plasma protein imbalances are an inherent characteristic of wounds. Powanda teaches that injuries elicit a number of metabolic and physiologic responses at the site of tissue damage and throughout the body, including increased hepatic synthesis of a number of plasma proteins, the acute phase response, which result in an increase in the plasma concentration of these proteins (p. 1, Col. 1). This reference teaches that some of plasma proteins localize specifically around the site of injury, while others accumulate at the wound seemingly as a result of greater capillary permeability (p. 1, Col. 1).
The claims are also drawn to preventative methods of treatment, as the specification (p. 9) it encompasses “preventative treatment, that is, treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder.” As such, the patient population that falls within those that can have protein imbalances treated does not need to be that which already have an imbalance. Additionally, the specification does not provide any objective measure of what is considered to be a protein imbalance, only the causes for the imbalance, which include trauma, subcutaneous trauma, burns and surgery, which all fall within the scope of wound repair.
As such, it would have been obvious to one of ordinary skill in the art at the time of the invention to have administered the composition of Copper to subject having protein imbalances as a result of a wound, as healing the wound necessarily treats plasma protein imbalance by treating the wound. One would be motivated to do so because Powanda teaches that healing wounds will result in plasma proteins to localize at the wound site, and Cooper teaches a composition for treating wounds, which enabling removal of deleterious proteins and contributing to the wound healing process causes proteins to be trapped at the wound site, and administering transferrin haptoglobin compositions will release the deleterious proteins at the wound site, allowing it to heal. As such, there is a reasonable expectation of success that the wound healing method of Cooper will also treat plasma protein imbalances.
Claims 1-3 are met because the same composition comprising 3.9% haptoglobin, 11% transferrin administered to treat subjects having a wound having the inherent protein imbalance described in Powanda. The concentration of the haptoglobin would have been obvious to optimize, based on the teachings of Cooper and what is known in the art about routine optimization.
The MPEP states: 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) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("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."); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Lab. Inc., 874 F.2d 804, 809, 10 USPQ2d 1843, 1848 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989)(Claimed ratios were obvious as being reached by routine procedures and producing predictable results); In re Kulling, 897 F.2d 1147, 1149, 14 USPQ2d 1056, 1058 (Fed. Cir. 1990)(Claimed amount of wash solution was found to be unpatentable as a matter of routine optimization in the pertinent art, further supported by the prior art disclosure of the need to avoid undue amounts of wash solution); and In re Geisler, 116 F.3d 1465, 1470, 43 USPQ2d 1362, 1366 (Fed. Cir. 1997)(Claims were unpatentable because appellants failed to submit evidence of criticality to demonstrate that that the wear resistance of the protective layer in the claimed thickness range of 50-100 Angstroms was "unexpectedly good"); Smith v. Nichols, 88 U.S. 112, 118-19 (1874) (a change in form, proportions, or degree "will not sustain a patent"); In re Williams, 36 F.2d 436, 438, 4 USPQ 237 (CCPA 1929) ("It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions."). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416, 82 USPQ2d 1385, 1395 (2007) (identifying "the need for caution in granting a patent based on the combination of elements found in the prior art.").
Claim 6 is met because the method of Cooper teaches that the composition comprises 2.7% albumin (Table 2 , example 2). Claim 8 is met because albumin must be either polymeric or monomeric. Claim 9 is met because Cooper teaches that the composition comprises 4.2% ceruplasmin. Claim 35 is met because the subject being treated will go through different stages of protein imbalance in the process of wound healing, as discussed by Cooper. Furthermore, the claim being drawn to preventative treatment means that the subject may be any subject that could incur a wound or be subjected to hemorrhagic shock, which does not exempt those that already have a wound, as prevention reads on any subject. Thus, claims 18 and 22 are met because the patient class includes preventative administration, which means that the protein balance and its eliciting effect could happen in the future and does not require the subject to have undergone the hemorrhagic shock to cause it. Claims 42 and 48 are met because Cooper teaches the addition of other active agents, such as antibiotics, anti-inflammatory agents, antiseptics and analgesics [0045, 0047, 0110, 0117].
Claim(s) 1-4, 6, 8, 11, 15, 18, 22, 30, 35, 42, 45 and 48 are rejected under 35 U.S.C. 103 as being unpatentable over Regan et al. (US2013/0012443) in view of Brinkman (US9,534,029).
Regan teaches methods of treating CNS hemorrhage, including intracranial hemorrhage, cerebral or intracerebral, intra-axial hemorrhage and intraventricular, epidural and subdural hemorrhage with protoporphyrin IX-Fe compounds and DC-Fe compounds [0009, 0010-0012]. This reference teaches that the compositions include protoporphyrin Dc-Fe bound to albumin, protoporphyrin IX-Fe bound to hemopexin and protoporphyrin IX-Fe [0012-0013]. This reference further teaches that IX-Fe may be bound to transferrin, in order to cross the blood brain barrier [0116]. Regan also teaches that subjects at risk for hemorrhage are those that have been diagnosed with having or at risk of having trauma [0092].
The difference between the prior art and the instant claims is that the prior art does not teach the claimed percentages of each component of the hemorrhagic treating composition and does not teach haptoglobin and transferrin administration together in a single composition.
Brinkman teaches methods of treating acute hemolytic conditions and/or a chronic hemolytic conditions, including hemolytic anemia, trauma, open heart surgery using and burns, with compositions that comprise purified transferrin, haptoglobin and hemopexin in a composition comprising at least 90% of the total protein (Col. 11, lines 2-15, lines 47-67; Col. 12-Col. 13). Brinkman further teaches these with a pharmaceutical carrier (spanning Col. 12-Col. 13). Brinkman further teaches method of purifying transferrin, haptoglobin and hemopexin from Cohn Factor IV, in which other plasma proteins, such as IgG, IgM are below detectable levels when characterized by immune-nephelometry (Example 1, Fig. 1, Col. 13, lines 50-67, Col 15, lines 47-56 and Col. 17, lines 5-19).
Brinkman also teaches methods of treating hemolysis and that that low red blood cell counts generally accompany aberrant Hb/heme levels (Spanning Col. 1-2). This reference teaches treating hemolysis with the same purified plasma protein compositions comprising transferrin, albumin, hemopexin and haptoglobin (Spanning Col. 1-2, Fig. 2 ). Brinkman further teaches that acute hemolytic conditions, including blood transfusions, hemolytic anemia, trauma, and open heart surgery, are all treatable with the protein compositions comprising at least 90% of a combination of these plasma proteins (Col. 13, lines 15-30, Col. 11, lines 2-5).
The difference between the prior art and the instant claims is that Brinkman does not teach administering the composition in a specific example that is reduced to practice for administering these compositions to a subject.
However, it would have been obvious to one of ordinary skill in the art to have taken Brinkman’s method of treating aberrant levels of blood protein due to hemolysis, with the transferrin and haptoglobin combination in a plasma based composition, and administered it to a subject in need of hemolytic treatment for various conditions. One would be motivated to do so because Brinkman teaches that compositions comprising transferrin, hemopexin and haptoglobin can be used for treating hemolytic conditions that require protein balance to be restored. As such, there is a reasonable expectation of success that the composition of Brinkman can be used effectively for treating plasma protein imbalances associated with various hemolytic conditions.
This renders obvious the limitations of claims 1-4, because it would have been obvious to optimize the percentages of the proteins taught by Brinkman, and any plasma imbalance meets the level of showing a protein imbalance because there is no objective threshold to measure this. Additionally, the claims are drawn to preventative methods (rendering it obvious to administer to any subject, as discussed above). Claims 6 and 8 are met because Brinkman also teaches adding albumin, and albumin must be either monomeric or polymeric (see above).Claims 11 and 22 and are met because Brinkman reads on the scope of prophylactic treatment.
Although the specific ranges of protein concentration are not taught by the prior art, it would have been obvious to optimize the percentages of the compositions taught by Brinkman, in order to treat or prevent hemorrhagic shock and the protein imbalances that accompany wounds and trauma. One would be motivated to do so because Regan teaches treating hemorrhagic shock, and both references teach treating trauma with similar protein mixtures comprising transferrin, haptoglobin, albumin and hemopexin. As such, there is a reasonable expectation of success that a subject that already has, or that may experience future trauma, protein imbalances and/or hemorrhagic shock, would be effectively treatable with optimized compositions comprising these plasma proteins.
Claim 15 is met because Brinkman teaches a method of purifying transferrin hemopexin and haptoglobin in a process with high yield, which renders the compositions “substantially free,” of immunogenic proteins. “Substantially free” is defined in the specification (p. 10) as less the .5%, and Brinkman teaches that other proteins were below detectable levels when characterized by immune-nephelometry (see example 1). Claim 18 is met because both references teach a method of treatment that falls within the scope of hemorrhagic shock preventative treatment, and Regan specifically teaches treating hemorrhagic shock. Claim 22 is met because both references teach treating trauma. Claim 30 is met because the specification describes “plasma expander,” as a “protein scavenging cocktail,” and Brinkman teaches that haptoglobin and hemopexin are heme scavenger proteins (Col. 1, lines 53-64). Claim 35 is met because any subject to which the composition is administered is a subject in which the treatment may be prophylactic. Claims 42 and 45 are met because Regan teaches that the active agent of the composition may be bound to albumin or transferrin for crossing the BBB. Claim 48 is met because Regan teaches additional active agents (e.g., IX-Fe), and Brinkman teaches other active protein agents, (e.g., other plasma proteins, such as hemopexin).
Claim(s) 1-3, 6, 8, 9, 13, 18, 22, 35, 42 and 48 are rejected under 35 U.S.C. 103 as being unpatentable over Cooper et al. (US2018/0353543; See ISR), in view of Powanda et al. (Surgery, Obstetrics and Gynecology, Vol. 153, 749-755, 1981), as applied to claims 1-4, 6, 8, 9, 15, 18, 22, 30 35 and 42 above, and as evidenced by Susin Pires et al. (US2022/0218834).
The teachings of Cooper and Powanda have been described supra.
Claim 13 is drawn to haptoglobin having an average molecular weight of 80kDa to 1,000kDa, which is the average molecular weight of haptoglobin, as evidence by Susin Pires (See claim 1; post priority date, cited here as evidentiary only). As such, claim 13 is met.
Conclusion
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/JEANETTE M LIEB/Primary Examiner, Art Unit 1654