1. A method of operating coupling circuitry that couples a network to a host, the host further configured for transfer of data between the host and at least one peer via the network according to a TCP connection-oriented protocol, the method comprising:
by the coupling circuitry, receiving indications corresponding to TCP connection establishment phase messages to the host from a nominal peer according to the connection-oriented protocol, wherein the indications corresponding to connection establishment phase messages are messages including TCP SYN information from the nominal peer;
by the coupling circuitry, processing each of the received indications by attempting to perform appropriate responsive processing in accordance with the connection-oriented protocol such that, when the nominal peer is an actual peer, the coupling circuitry interoperates with the actual peer to perform TCP connection establishment phase protocol processing of an attempted stateful connection between the host and the actual peer according to the connection-oriented protocol to accomplish establishment of a stateful TCP connection, wherein attempting to perform appropriate responsive processing includes providing at least one message including TCP SYN+ACK information to the nominal peer and thereafter receiving at least one message including an ACK to the TCP SYN+ACK information from the nominal peer, wherein accomplishing establishment of the stateful connection includes generating TCP connection state data in the coupling circuitry characterizing the established stateful TCP connection, wherein the TCP connection state data includes a state of the established stateful TCP connection; and
by the coupling circuitry, for each of the established stateful TCP connections, causing the generated TCP connection state data characterizing that established stateful TCP connection to be provided from the coupling circuitry to be accessible to a TCP protocol processing stack of the host based on a determination that the TCP connection has been successfully established and without the coupling circuitry itself handing any data transfer phase processing of the established TCP connection prior to causing the generated TCP connection state data to be accessible to the TCP protocol processing stack of the host, whereby the generated TCP connection state data is usable by the host to handle data transfer phase protocol processing of that established stateful TCP connection, for transfer of data between the host and at least one peer via the network, wherein prior to each connection having been established by interoperation of the coupling circuitry with the actual peer and the resulting generated TCP connection state data having been provided from the coupling circuitry to be accessible to the protocol processing stack of the host for data transfer processing of that TCP connection, resources of the host for that TCP connection are not allocated or involved.
2. The method of claim 1, wherein:
for a first particular connection establishment phase message including ACK of TCP SYN+ACK information from a nominal peer that, according to the connection-oriented protocol is to be preceded by a corresponding second particular connection establishment message including a TCP SYN information from a nominal peer, determining that the appropriate response is no response when there is no preceding corresponding second particular connection establishment message.
3. The method of claim 1, further comprising:
by the host, receiving the generated TCP connection state data characterizing the state of that established stateful TCP connection and handling the data transfer phase processing of that established stateful TCP connection using the received generated TCP connection state data characterizing the state of that established stateful TCP connection, for transfer of data between the host and at least one peer via the network.
4. The method of claim 1, wherein:
the coupling circuitry is at least a portion of circuitry comprising an intelligent network adaptor that is a network interface card.
5. The method of claim 1, wherein:
the coupling circuitry includes a combination of hardware and a programmed microprocessor.
6. The method of claim 1, wherein:
the coupling circuitry does not provide the host particular generated TCP connection state data characterizing an established stateful TCP connection until after the TCP stateful connection is established.
7. A method of operating coupling circuitry that couples a network to a host, the host further configured for transfer of data between the host and at least one peer via the network using at least one stateful connection between the host and the at least one peer according to a connection-oriented protocol, wherein the connection-oriented protocol includes a definition of at least a connection establishment phase and of a data transfer phase, the definition of the connection establishment phase including at least a first message that is a request by a peer to connect with the host, a second message that is a response by the host to the peer acknowledging the first message, and a third message that is a response from the peer to the host acknowledging the second message, wherein a proper exchange of the first message, the second message and the third message according to the connection-oriented protocol is necessary to establish a stateful connection between the peer and the host, the method comprising:
by the coupling circuitry, receiving indications each corresponding to a nominal connection establishment attempt first message by a nominal peer to establish a stateful connection with the host according to the connection-oriented protocol;
by the coupling circuitry, for each of the received nominal stateful connection establishment attempts first messages, processing that received nominal stateful connection establishment attempt first message by providing an appropriate response second message, according to the connection-oriented protocol, to that connection establishment attempt, such that at least some of the appropriate second message each result in receipt of an appropriate third message and therefore an established stateful connection; and
by the coupling circuitry, for each of the established stateful connections as a result of the coupling circuitry interoperating with a peer to accomplish establish phase processing for that stateful connection, causing generated connection state data characterizing that established stateful connection and including a state of that established stateful connection to be provided from the coupling circuitry to be accessible to a protocol processing stack of the host based on a determination that the connection has been successfully established and without the coupling circuitry itself handing any data transfer phase processing of the established connection prior to causing the generated connection state data to be accessible to the protocol processing stack of the host, whereby the generated connection state data is usable by the host to handle data transfer phase protocol processing of that established stateful connection, for transfer of data between the host and at least one peer via the network,
wherein prior to each connection having been established by interoperation of the coupling circuitry with the actual peer and the resulting generated connection state data having been provided from the coupling circuitry to be accessible to the protocol processing stack of the host for data transfer processing of that connection, resources of the host for that connection are not allocated or involved.
8. The method of claim 7, further comprising:
by the host, receiving the generated connection state data characterizing the state of that established stateful connection and handling the data transfer phase processing of that established stateful connection, for transfer of data between the host and at least one peer via the network, using the received generated connection state data characterizing the state of that established stateful connection.
9. The method of claim 7, wherein:
the connection-oriented protocol is TCPIP.
10. The method of claim 7, wherein:
the coupling circuitry is at least a portion of circuitry comprising an intelligent network adaptor.
11. The method of claim 7, wherein:
the coupling circuitry includes a combination of hardware and a programmed microprocessor.
12. The method of claim 7, wherein:
the coupling circuitry does not provide the host any of the particular generated connection state data characterizing an established a stateful connection until after the stateful connection is established by the coupling circuitry.
13. An intelligent network adaptor to couple a network to a host that is configured for transfer of data between the host and at least one peer via the network according to a connection-oriented protocol, wherein the connection-oriented protocol includes a definition of at least a connection establishment phase and of a data transfer phase, the definition of the connection establishment phase including at least a first message that is a request by a peer to connect with the host, a second message that is a response by the host to the peer acknowledging the first message, and a third message that is a response from the peer to the host acknowledging the second message, wherein a proper exchange of the first message, the second message and the third message according to the connection-oriented protocol is necessary to establish a stateful connection between the peer and the host, the network adaptor comprising a processor and a memory, wherein the processor is configured to process instructions in the memory to:
receive indications of attempts to establish stateful connections with a host according to the connection-oriented protocol, wherein the indications of attempts are indications of first messages of the connection establishment phase of the connection-oriented protocol; process each of the received indications by interoperating with the at least one peer, attempting to establish a stateful connection to a nominal peer indicated by said received indication, by attempting to exchange with the nominal peer second and third messages of the connection establishment phase of the connection-oriented protocol, such that, for a genuine attempt by a peer to establish a stateful connection with the host, the intelligent network adaptor successfully interoperates with the peer to perform establishment-phase protocol processing of the attempted stateful connection between the peer and the host according to the connection-oriented protocol to actually accomplish establishment of the stateful connection, wherein accomplishing establishment of the stateful connection includes generating connection state data in the network adaptor during the connection establishment phase of the connection according to the connection-oriented protocol, the connection state characterizing the established stateful connection and including a state of the established stateful connection; and
for each of the established stateful connections, cause the generated connection state data characterizing that established stateful connection to be provided from the coupling circuitry to be accessible to a protocol processing stack of the host based on a determination that the connection has been successfully established and without the coupling circuitry itself handing any data transfer phase processing of the established connection prior to causing the generated connection state data to be accessible to the protocol processing stack of the host, whereby the generated connection state data is usable by the host to handle data transfer phase protocol processing of that established stateful connection, for transfer of data between the host and at least one peer via the network,
wherein prior to each connection having been established by interoperation of the intelligent network adaptor with the actual peer and the resulting generated connection state data having been provided from the intelligent network adaptor to be accessible to the protocol processing stack of the host for data transfer processing of that connection, resources of the host for that established stateful connection are not allocated or involved.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. A method for treating or preventing a bone degenerative disease or disorder in a mammal in need thereof, comprising administering to the mammal an effective amount of a composition comprising an Activin Receptor Type MB (ActRIIB) fusion polypeptide, wherein the fusion polypeptide comprises:
(a) an amino acid sequence chosen from:
(i) an amino acid sequence that is at least 80% identical to amino acids 19 to 134 of SEQ ID NO:1, or a fragment thereof that specifically binds GDF-8 or BMP-11; and
(ii) an amino acid sequence that is at least 80% identical to amino acids 23 to 138 of SEQ ID NO:3, or a fragment thereof that specifically binds GDF-8 or BMP-11; and
(b) an Fc portion of an antibody.
2. (canceled)
3. A method for treating or preventing a bone degenerative disease or disorder in a mammal in need thereof, comprising administering to the mammal an effective amount of a composition comprising an ActRIIB fusion polypeptide, wherein the fusion polypeptide comprises:
(a) an amino acid sequence that is encoded by a nucleic acid that hybridizes under stringent conditions to the complement of nucleic acids 67-414 of SEQ ID NO:4, or a fragment thereof that encodes a polypeptide that specifically binds GDF-8 or BMP-11; and
(b) an Fc portion of an antibody.
4. (canceled)
5. (canceled)
6. The method of claim 1, wherein the bone degenerative disease or disorder is chosen from at least one of: osteoporosis, glucocorticoid-induced osteoporosis, osteopenia, osteoarthritis, osteoporosis-related fractures, low bone mass due to chronic glucocorticoid therapy, premature gonadal failure, androgen supression, vitamin D deficiency, secondary hyperparathryoidism, nutritional deficiencies, bone healing, fracture repair, spinal fusion, decline in bone mass or microarchiteture and strength due to estrogen deficiency, and anorexia nervosa.
7. The method of claim 1, wherein the bone degenerative disease or disorder is osteoarthritis or osteoporosis.
8. (canceled)
9. The method of claim 1, wherein the amino acid sequence comprises at least 70 contiguous amino acids.
10. (canceled)
11. The method of claim 1, wherein the amino acid sequence is truncated.
12. (canceled)
13. (canceled)
14. The method of claim 1, wherein the ActRIIB fusion polypeptide comprises amino acids 23 to 119 of SEQ ID NO:3.
15. (canceled)
16. (canceled)
17. (canceled)
18. The method of claim 1, wherein the ActRIIB fusion polypeptide comprises an amino acid sequence that is at least 80% identical to SEQ ID NO:3.
19. The method of claim 1, wherein the ActRIIB fusion polypeptide comprises an Fc portion of IgG.
20. (canceled)
21. The method of claim 19, wherein the Fc portion comprises amino acids 148 to 378 of SEQ ID NO:3.
22. The method of claim 1, wherein the ActRIIB fusion polypeptide comprises an antibody constant region.
23. The method of claim 1, wherein the Fc portion is modified to reduce effector function.
24-35. (canceled)
36. The method of claim 1, wherein the circulatory half-life of the ActRIIB fusion polypeptide exceeds 14 days.
37. The method of claim 1, wherein the ActRIIB fusion polypeptide specifically binds to GDF-8 with a Ka higher than 106 M\u20331.
38. The method of claim 1, wherein the ActRIIB fusion polypeptide specifically binds to GDF-8 with a Ka higher than 108 M\u20331.
39. The method of claim 1, wherein the ActRIIB fusion polypeptide specifically binds to GDF-8 with an ED50 of 15 ngml.
40. The method of claim 1, wherein the ActRIIB fusion polypeptide specifically binds to BMP-11 with an ED50 of 40 ngml.
41. The method of claim 1, wherein the ActRIIB fusion polypeptide has an IC50 for inhibiting GDF-8 in the range of 0.07 nM to 0.1 nM.
42. The method of claim 1, wherein the ActRIIB fusion polypeptide is administered at an effective amount chosen from 1 pgkg to 20 mgkg, 1 pgkg to 10 mgkg, 1 pgkg to 1 mgkg, 10 pgkg to 1 mgkg, 10 pgkg to 100 pgkg, 100 pg to 1 mgkg, and 500 pgkg to 1 mgkg.
43. The method of claim 1, wherein the ActRIIB fusion polypeptide is administered at an effective amount chosen from:
(1) a first dose at 1\xd7IC50, followed by a second dose at 0.5\xd7IC50, wherein the second dose is administered 2 weeks after the first dose;
(2) a first dose of 10\xd7IC50, followed by a second dose at 5\xd7IC50, wherein the second dose is administered 2 weeks after the first dose; and
(3) a first dose of 100\xd7IC50, followed by a second dose at 50\xd7IC50, wherein the second dose is administered 2 weeks after the first dose.